Tau-protein targeting protacs and associated methods of use

ABSTRACT

The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present disclosure is a divisional application of United States(U.S.) patent application Ser. No. 15/801,243, filed 1 Nov. 2017,published as U.S. Patent Application Publication No. 2018/0125821 A1,which claims priority to and the benefit of U.S. Provisional ApplicationNo. 62/415,830, filed on 1 Nov. 2016, which is incorporated herein byreference in its entirety.

INCORPORATION BY REFERENCE

U.S. patent application Ser. No. 15/230,354, filed on Aug. 5, 2016; andU.S. Patent Application Ser. No. 62/406,888, filed on Oct. 11, 2016; andU.S. patent application Ser. No. 14/686,640, filed on Apr. 14, 2015,published as U.S. Patent Application Publication No. 2015/0291562; andU.S. patent application Ser. No. 14/792,414, filed on Jul. 6, 2015,published as U.S. Patent Application Publication No. 2016/0058872; andU.S. patent application Ser. No. 14/371,956, filed on Jul. 11, 2014,published as U.S. Patent Application Publication No. 2014/0356322; andU.S. patent application Ser. No. 15/074,820, filed on Mar. 18, 2016,published as U.S. Patent Application Publication No. 2016/0272639, areincorporated herein by reference in their entirety. Furthermore, allreferences cited herein are incorporated by reference herein in theirentirety.

BACKGROUND 1. Field of the Discovery

The present description relates to bifunctional compounds, which areuseful for modifying intracellular ubiquitination and subsequentdegradation of target polypeptides and proteins, in particular, Tauprotein. Compounds of the present disclosure place targetprotein/polypeptide in proximity to a ubiquitin ligase to effect theubiquitination and degradation (and inhibition) of Tau protein.

2. Background Information

Most small molecule drugs bind enzymes or receptors in tight andwell-defined pockets. On the other hand, protein-protein interactionsare notoriously difficult to target using small molecules due to theirlarge contact surfaces and the shallow grooves or flat interfacesinvolved. E3 ubiquitin ligases (of which hundreds are known in humans)confer substrate specificity for ubiquitination, and therefore, are moreattractive therapeutic targets than general proteasome inhibitors due totheir specificity for certain protein substrates. The development ofligands of E3 ligases has proven challenging, in part due to the factthat they must disrupt protein-protein interactions. However, recentdevelopments have provided specific ligands which bind to these ligases.For example, since the discovery of nutlins, the first small molecule E3ligase inhibitors, additional compounds have been reported that targetE3 ligases, but the field remains underdeveloped.

One E3 ligase with exciting therapeutic potential is the vonHippel-Lindau (VHL) tumor suppressor, the substrate recognition subunitof the E3 ligase complex VCB, which also consists of elongins B and C,Cul2 and Rbx1. The primary substrate of VHL is Hypoxia Inducible Factor1α (HIF-1α), a transcription factor that upregulates genes such as thepro-angiogenic growth factor VEGF and the red blood cell inducingcytokine erythropoietin in response to low oxygen levels. The firstsmall molecule ligands of Von Hippel Lindau (VHL) to the substraterecognition subunit of the E3 ligase were generated, and crystalstructures were obtained confirming that the compound mimics the bindingmode of the transcription factor HIF-la, the major substrate of VHL.

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance. Cereblon forms an E3 ubiquitin ligasecomplex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A),and regulator of cullins 1 (ROC1). This complex ubiquitinates a numberof other proteins. Through a mechanism which has not been completelyelucidated, cereblon ubquitination of target proteins results inincreased levels of fibroblast growth factor 8 (FGF8) and fibroblastgrowth factor 10 (FGF10). FGF8 in turn regulates a number ofdevelopmental processes, such as limb and auditory vesicle formation.The net result is that this ubiquitin ligase complex is important forlimb outgrowth in embryos. In the absence of cereblon, DDB1 forms acomplex with DDB2 that functions as a DNA damage-binding protein.

The Tau protein is an abundant protein in the central nervous systemprimarily found in neuronal cells, although Tau is expressed at lowerlevels in other cells of the central nervous system. In a healthyneuron, Tau binds to microtubules and regulates microtubule stability,which is critical for axonal outgrowth and neuronal plasticity. Whenpathologically altered, Tau molecules are not able to stabilizemicrotubules and are prone to form insoluble aggregates. Once the Tauprotein forms insoluble aggregates in cells, cellular dysfunctionoccurs, axonal transport is compromised, and neuronal loss ensues.Accumulation of abnormal Tau aggregates in neurons is an importantpathological signature in multiple neurodegenerative disorders includingAlzheimer's disease. In certain pathological conditions, Tau aggregationresults in paired-helical filaments (PHFs), straight filaments (SFs)and/or neurofibrillary tangles (NFTs). The accumulation of PHFs and NFTsin neurons directly correlates with microtubule dysfunction and neuronaldegeneration. Neurons containing tau PHFs, SFs, and or NFTs activatediverse cellular mechanisms to try and rid the cell of the abnormalprotein aggregates.

More recent studies suggest that, instead of the large insolublefilaments, soluble Tau oligomers might play a more critical role in theonset and progression of disease prior to the development of PHF- orNFT-induced neurotoxicity. Oligomeric species of Tau may act as seedsfor the aggregation of native Tau, thereby promoting neurotoxic Tauaggregation. Accumulating evidence has suggested that Tau aggregates canbe transmitted from one cell to another by propagating in a prion-likemanner.

Tau alteration and dysfunction and extensive neuron loss has long beenassociated with several neurodegenerative diseases now collectivelycalled tauopathies.

The term “tauopathy” or “tauopathies” refers herein to a class ofneurodegenerative diseases associated with the pathological aggregationof Tau protein in neurofibrillary or gliofibrillary tangles in the humanbrain. Examples of tauopathies include but are not limited to AD, Down'ssyndrome, frontotemporal lobular dementia (FTLD), cotricobasaldegeneration (CBD) and progressive supranuclear palsy (PSP)

Due to its pathological significance in multiple neurodegenerativediseases, Tau is an important therapeutic target. Preventing Tauaggregation becomes a potential strategy to treat neurodegenerativedisorders associated with Tau. So far, great effort has been made toidentify molecular mechanisms of Tau aggregation and find therapeuticsto halt the progression of neurodegeneration.

Tau aggregation inhibitors which demonstrated promising pre-clinicaldata have proven ineffective in recent clinical trials for the treatmentof various tauopathies. Therefore, a need exists in the art foreffective treatments of diseases and conditions that are related to theaggregation of Tau in neurodegenerative disorders such as tauopathies.

SUMMARY

The present disclosure describes bifunctional compounds, includingcompositions comprising the same, which function to recruit endogenousproteins to an E3 ubiquitin ligase for ubiquitination and subsequentdegradation, and methods of using the same. In particular, the presentdisclosure provides bifunctional or proteolysis targeting chimeric(PROTAC) compounds, which find utility as modulators of targetedubiquitination and degradation of Tau protein aggregates. In addition,the description provides methods of using an effective amount of thecompounds as described herein for the treatment or amelioration ofdisease conditions due to accumulation or aggregation of Tau proteinssuch as tauopathies. These diseases or disorders include but are notlimited to neurological or neurodegenerative disorders.

Thus, in one aspect, the disclosure provides compounds which function torecruit endogenous proteins, e.g., Tau, to E3 Ubiquitin Ligase forubiquintination and degradation.

In any of the embodiments, the compounds have the following generalstructures

PTM-L-ULM

In certain embodiments, the compounds have the following generalstructures (A)

PTM-L-VLM  (A)

In certain embodiments, the compounds have the following generalstructures (B)

PTM-L-CLM  (B)

wherein, PTM represents protein targeting moiety, ULM represents E3ubiquitin ligase targeting moiety including but not limited to VLM (VHLligase-binding moiety) and CLM (cereblon ligase-binding moiety) and Lrepresents a linker, e.g., a bond or a chemical linker moiety. As wouldbe understood by the skilled artisan, the bifunctional compounds asdescribed herein can be synthesized such that the number and position ofthe respective functional moieties can be varied as desired.

In certain embodiments, the PTMs in structure (A) are the ligands thatbind to Tau as well as VHL E3 ubiquitin ligase.

In certain embodiments, the PTMs in structure (B) are the ligands thatbind to Tau as well as CLM E3 ubiquitin ligase.

In certain embodiments, the compounds as described herein comprisemultiple ULMs, multiple PTMs, multiple chemical linkers or a combinationthereof. In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., neuronal disease. In yet anotheraspect, the present disclosure provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bifunctional compoundas described herein comprising an ULM and a PTM, which may be linkedthrough a linker moiety, as otherwise described herein, wherein the ULMis coupled to the PTM and wherein the ULM recognizes a ubiquitin pathwayprotein e.g., an ubiquitin ligase, such as an E3 ubiquitin ligase morepreferably VLM and CLM and the PTM recognizes the target protein (TBM)such that degradation of the target protein will occur when the targetprotein (e.g., Tau) is placed in proximity to the ubiquitin ligase, thusresulting in degradation of the target protein, inhibition of itseffects and the control of protein levels. In another aspect, the targetprotein is Tau. The present disclosure provides treatment of a diseasestate or condition through control of protein levels, i.e. by loweringthe level of that protein (e.g., Tau protein) in the cells of a patientvia degradation.

In particular, PTM are molecules that bind to Tau protein (TBM), and ULMare molecules that bind to VHL E3 ubiquitin ligase and/or to CLM E3ubiquitin ligase with the following general structures:

TBM-L-VLM/CLM

The PTM (protein-targeting moiety) of the PROTACs of current disclosureis represented by the general formulas I, II, III, IV, V, VI, VII, VIII,XI, X, and XI:

wherein:

-   -   A, B, C, D, E, and F are each independently selected from an        optionally substituted 5- or 6-membered aryl or heteroaryl ring,        an optionally substituted 4- to 7-membered cycloalkyl or a        heterocycloalkyl, where contact between circles indicates ring        fusion; and    -   L_(PTM) is selected from a bond, an alkyl, an alkenyl or an        alkynyl, optionally interrupted by one or more rings (i.e.,        cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or        more functional groups which could include —O—, —S—, —NR¹        _(PTM)— (where R¹ _(PTM) is selected from H or alkyl), —N═N—,        —S(O)—, —SO₂—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO₂—, —NHC(O)NH—,        —NHC(O)O—, —OC(O)NH—, wherein the said functional group can be        optionally located at either end of the linker (i.e., directly        adjacent to the A, B, C, D, E, or F rings).

The above mentioned aryl and heteroaryl rings can be optionallysubstituted with 1-3 substituents each independently selected fromalkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy,amino, alkylamino, dialkylamino, acylamino, trifluomethyl, and cyano,wherein the said alkyl and alkenyl groups can be further substituted.

In any aspect or embodiment described herein, at least one of A, B, C,F, or a combination thereof is selected from optionally substituted 5-or 6-membered aryl or heteroaryl rings.

In certain embodiments of the current disclosure, the PTM is representedby Formula I and/or II, where A, B and C are 5- or 6-membered fused arylor heteroaryl rings, L_(PTM) is selected from a bond or an alkyl, and Dis selected from a 6-membered aryl, heteroaryl or heterocycloalkyl,wherein A, B, C and D are optionally substituted with alkyl, haloalkyl,halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,trifluoromethyl, or cyano.

In other embodiments, the PTM is represented by Formula III and/or IV,wherein A, B and C are 5- or 6-membered fused aryl or heteroaryl rings,L_(PTM) is selected from a bond or an alkyl, and D and E are 5- or6-membered fused aryl or heteroaryl rings, and wherein A, B, C, D and Eare optionally substituted with alkyl, haloalkyl, halogen, hydroxyl,alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.

In certain other embodiments of the current disclosure, the PTM isrepresented by Formula I, wherein A is a phenyl or a 6-memberedheteroaryl ring, B is a 5-membered heteroaryl ring, C is a phenyl or a6-membered heteroaryl ring, L_(PTM) is a bond, and D is a 6-memberedheteroaryl or a 6-membered heterocycloalkyl ring, wherein each A, B, Cand D is optionally independently substituted with alkyl, haloalkyl,halogen, hydroxyl, alkoxy, amino, dialkylamino, trifluoromethyl, orcyano, with the proviso that a nitrogen atom of any of the A, B, C and Drings is not directly connected to a heteroatom or to a carbon atom ofthe L_(PTM), to which another heteroatom is directly attached.

It will be understood that the general structures are exemplary and therespective moieties can be arranged spatially in any desired order,number or configuration.

In further embodiments, the description provides a bifunctional compoundhaving a structure selected from the group consisting of Compounds 1-330(e.g., a compound selected from Tables 1 and 2), a salt, a polymorph,and a prodrug thereof.

In further embodiments, the description provides a bifunctional compoundhaving a structure selected from the Table 1 or Table 2 (e.g., achemical structure selected from Compounds 1-330), a salt, a polymorph,and a prodrug thereof.

In another aspect, the description provides compositions comprisingcompounds as described herein, and a pharmaceutically acceptablecarrier. In certain embodiments, the compositions are therapeutic orpharmaceutical compositions comprising an effective amount of a compoundas described herein and a pharmaceutically acceptable carrier. Incertain embodiments, the therapeutic or pharmaceutical compositionscomprise an additional biologically active agent, e.g., an agenteffective for the treatment of neuronal disease.

In any of the aspects or embodiments described herein, the therapeuticcompositions comprising compounds described herein can be in anysuitable dosage form, e.g., solid, or liquid, and configured to bedelivered by any suitable route, e.g., oral, parenteral, intravenous,intraperitoneal, subcutaneous, intramuscular, etc.

In another aspect, the description provides methods of modulating Tauprotein, their ubiquitination and the subsequent degradation in asubject, e.g., a cell, a tissue, mammal, or human patient, the methodcomprising administering an effective amount of a compound as describedherein or a composition comprising an effective amount of the same to asubject, wherein the compound or composition comprising the same iseffective in modulating Tau ubquitination and degradation in thesubject.

In yet another aspect, the description provides methods of treating orameliorating a symptom of a disease related to TAU activity in asubject, e.g., a cell, a tissue, mammal, or human patient, the methodcomprising administering an effective amount of a compound as describedherein or a composition comprising an effective amount of the same to asubject in need thereof, wherein the compound or composition comprisingthe same is effective in treating or ameliorating a symptom of a diseaserelated to TAU activity in the subject. In certain embodiments, thedisease to be treated is neurological or neurodegenerative disease, e.g.Alzheimer, Parkinson, Dementia etc.

In a preferred embodiment, the subject is a human.

In an additional aspect, the description provides methods foridentifying the effects of the degradation of proteins of interest in abiological system using compounds according to the present disclosure.

Where applicable or not specifically disclaimed, any one of theembodiments described herein are contemplated to be able to combine withany other one or more embodiments, even though the embodiments aredescribed under different aspects of the disclosure. As such, thepreceding general areas of utility are given by way of example only andare not intended to be limiting on the scope of the present disclosureand appended claims. Additional objects and advantages associated withthe compositions, methods, and processes of the present disclosure willbe appreciated by one of ordinary skill in the art in light of theinstant claims, description, and examples. For example, the variousaspects and embodiments of the disclosure may be utilized in numerouscombinations, all of which are expressly contemplated by the presentdescription. These additional advantages, objects, and embodiments areexpressly included within the scope of the present disclosure. Thepublications and other materials used herein to illuminate thebackground of the disclosure, and in particular cases, to provideadditional details respecting the practice, are incorporated byreference.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate several embodiments of the presentdisclosure and, together with the description, serve to explain theprinciples of the disclosure. The drawings are only for the purpose ofillustrating an embodiment of the disclosure and are not to be construedas limiting the disclosure. Further objects, features and advantages ofthe disclosure will become apparent from the following detaileddescription taken in conjunction with the accompanying figures showingillustrative embodiments of the disclosure, in which:

The FIGURE shows total tau levels in hippocampal homogenates. Data aredisplayed as scattered dot blot. Statistically significant differencesbetween the test item (TI) treated groups versus the vehicle controlgroup according to One-way ANOVA followed by Dunneett's MultipleComparison Test are indicated by asterisk **p<0.01, *p<0.05.

DETAILED DESCRIPTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present disclosure. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. All publications, patent applications, patents,figures and other references mentioned herein are expressly incorporatedby reference in their entirety.

The present description relates to the surprising and unexpecteddiscovery that an E3 ubiquitin ligase protein can ubiquitinate a targetprotein once the E3 ubiquitin ligase protein and the target protein arebrought into proximity by a chimeric construct (e.g., PROTAC) asdescribed herein, which binds the E3 ubiquitin ligase protein (e.g., VHLand cereblon) and the target protein e.g., TAU. Accordingly, the presentdescription provides compounds, compositions comprising the same andassociated methods of use for ubiquitination and degradation of a chosentarget protein.

The following terms are used to describe the present disclosure. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present disclosure.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the disclosure. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the disclosure, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the disclosure.

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e., “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.”

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anonlimiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stereoisomers, including optical isomers (enantiomers) and otherstereoisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives (including prodrug forms) thereof whereapplicable, in context. Within its use in context, the term compoundgenerally refers to a single compound, but also may include othercompounds such as stereoisomers, regioisomers and/or optical isomers(including racemic mixtures) as well as specific enantiomers orenantiomerically enriched mixtures of disclosed compounds. The term alsorefers, in context to prodrug forms of compounds which have beenmodified to facilitate the administration and delivery of compounds to asite of activity. It is noted that in describing the present compounds,numerous substituents and variables associated with same, among others,are described. It is understood by those of ordinary skill thatmolecules which are described herein are stable compounds as generallydescribed hereunder.

When the bond

is shown, both a double bond and single bond are represented within thecontext of the compound shown.

The term “patient” or “subject” is used throughout the specification todescribe an animal, preferably a human or a domesticated animal, to whomtreatment, including prophylactic treatment, with the compositionsaccording to the present disclosure is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal, including a domesticated animal such as a dog or cat ora farm animal such as a horse, cow, sheep, etc. In general, in thepresent disclosure, the term patient refers to a human patient unlessotherwise stated or implied from the context of the use of the term.

The term “effective” is used to describe an amount of a compound,composition or component which, when used within the context of itsintended use, effects an intended result. The term effective subsumesall other effective amount or effective concentration terms, which areotherwise described or used in the present application.

The term “Ubiquitin Ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, cereblonis an E3 Ubiquitin Ligase protein that alone or in combination with anE2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase is involved in polyubiquitination suchthat a second ubiquitin is attached to the first; a third is attached tothe second, and so forth. Polyubiquitination marks proteins fordegradation by the proteasome. However, there are some ubiquitinationevents that are limited to mono-ubiquitination, in which only a singleubiquitin is added by the ubiquitin ligase to a substrate molecule.Mono-ubiquitinated proteins are not targeted to the proteasome fordegradation, but may instead be altered in their cellular location orfunction, for example, via binding other proteins that have domainscapable of binding ubiquitin. Further complicating matters, differentlysines on ubiquitin can be targeted by an E3 to make chains. The mostcommon lysine is Lys48 on the ubiquitin chain. This is the lysine usedto make polyubiquitin, which is recognized by the proteasome.

The term “protein target moiety” or PTM is used to describe a smallmolecule which binds to a target protein or other protein or polypeptideof interest and places/presents that protein or polypeptide in proximityto an ubiquitin ligase such that degradation of the protein orpolypeptide by ubiquitin ligase may occur. Non-limiting examples ofsmall molecule target protein binding moieties include compoundstargeting Tau protein.

The term “target protein” is used to describe a protein or polypeptide,which is a target for binding to a compound according to the presentdisclosure and degradation by ubiquitin ligase hereunder. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. These binding moieties are linked to ULM groups throughlinker groups L.

Tau protein target may be used in screens that identify compoundmoieties which bind to the protein and by incorporation of the moietyinto compounds according to the present disclosure, the level ofactivity of the protein may be altered for therapeutic end result.

The term “disease state or condition” is used to describe any diseasestate or condition wherein protein dysregulation (i.e., the amount ofprotein expressed in a patient is elevated) occurs and where degradationof Tau protein in a patient may provide beneficial therapy or relief ofsymptoms to a patient in need thereof. In certain instances, the diseasestate or condition may be cured.

Disease states or conditions which may be treated using compoundsaccording to the present disclosure include neuronal disease, forexample, neurodegeneration, Huntington's disease and muscular dystrophy,Parkinson's disease, Alzheimer's disease, Batten disease, Injuries tothe spinal cord and brain, Seizure disorders, epilepsy, brain tumors,meningitis, autoimmune diseases such as multiple sclerosis,Neurofibromatosis, Depression, Amyotrophic Lateral Sclerosis,Arteriovenous Malformation, Brain Aneurysm, Dural ArteriovenousFistulae, Headache, Memory Disorders, Peripheral Neuropathy,Post-Herpetic Neuralgia, Spinal Cord Tumor, Stroke.

The term “neurological disorder” or “neurological disorders”, as usedherein, refers to any disorder, disease, and/or syndrome due to orresulting from neurologic, psychiatric, psychological, and/orcerebrovascular symptomology or origin. The term “neurological disorder”or “neurological disorders”, as used herein, also refers to diseases,disorder or condition of the brain and nervous system or psychiatricdisorders or conditions. Neurological disorders include, but are notlimited to Absence of the Septum Pellucidum, Acquired EpileptiformAphasia, Acute Disseminated Encephalomyelitis, ADHD, Adie's Pupil,Adie's Syndrome, Adrenoleukodystrophy, Agenesis of the Corpus Callosum,Agnosia, Aicardi Syndrome, AIDS-Neurological Complications, AlexanderDisease, Alpers' Disease, Alternating Hemiplegia, Alzheimer's Disease,Amyotrophic Lateral Sclerosis, Anencephaly, Aneurysm, Angelman Syndrome,Angiomatosis, Anoxia, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis,Arnold-Chiari Malformation, Arteriovenous Malformation, AspergerSyndrome, Ataxia, Ataxia, Telangiectasia, Ataxias andCerebellar/Spinocerebellar Degeneration, Attention Deficit-HyperactivityDisorder, Autism, Autonomic Dysfunction, Back Pain, Barth SyndromeBatten Disease, Becker's Myotonia, Behcet's Disease, Bell's Palsy,Benign Essential Blepharospasm, Benign Focal Amyotrophy, BenignIntracranial Hypertension, Bernhardt-Roth Syndrome, Binswanger'sDisease, Blepharospasm, Bloch-Sulzberger Syndrome, Brachial Plexus BirthInjuries, Brachial Plexus Injuries, Bradbury-Eggleston Syndrome, Brainand Spinal Tumors, Brain Aneurysm, Brain Injury, Brown-Sequard Syndrome,Bulbospinal Muscular Atrophy, Canavan Disease, Carpal Tunnel SyndromeCausalgia, Cavernomas, Cavernous Angioma, Cavernous Malformation,Central Cervical Cord Syndrome, Central Cord Syndrome, Central PainSyndrome, Cephalic Disorders, Cerebellar Degeneration, CerebellarHypoplasia, Cerebral Aneurysm, Cerebral Arteriosclerosis, CerebralAtrophy, Cerebral Beriberi, Cerebral Gigantism, Cerebral Hypoxia,Cerebral Patsy, Cerebro-Oculo-Facio-Skeletal Syndrome,Charcot-Marie-Tooth Disease, Chiari Malformation, Chorea,Choreoacanthocytosis, Chronic Inflammatory Demyelinating Polyneuropathy(CIDP), Chronic Orthostatic Intolerance, Chronic Pain Cockayne SyndromeType II, Coffin Lowry Syndrome, COFS, Colpocephaly, Coma and PersistentVegetative State, Complex Regional Pain Syndrome, Congenital FacialDiplegia, Congenital Myasthenia, Congenital Myopathy, CongenitalVascular Cavernous, Malformations, Corticobasal Degeneration, CranialArteritis, Craniosynostosis, Creutzfeldt-Jakob Disease, CumulativeTrauma Disorders, Cushing's Syndrome, Cytomegalic Inclusion BodyDisease, Cytomegalovirus Infection, Dancing Eyes-Dancing Feet Syndrome,Dandy-Walker Syndrome, Dawson Disease, De Morsier's Syndrome, Deep BrainStimulation for Parkinson's Disease, Dejerine-Klumpke Palsy, Dementia,Dementia-Multi-Infarct, Dementia-Semantic, Dementia-Subcortical,Dementia With Lewy Bodies, Dentate Cerebellar Ataxia, DentatorubralAtrophy, Dermatomyositis, Developmental Dyspraxia, Devic's Syndrome,Diabetic Neuropathy, Diffuse Sclerosis, Dysautonomia, Dysgraphia,Dyslexia, Dysphagia, Dyspraxia, Dyssynergia Cerebellaris, Myoclonica,Dyssynergia Cerebellaris Progressiva, Dystonias, Early InfantileEpileptic, Encephalopathy, Empty Sella Syndrome, EncephalitisLethargica, Encephaloceles, Encephalopathy, EncephalotrigeminalAngiomatosis, Epilepsy, Erb-Duchenne and Dejerine-Klumpke Palsies, Erb'sPalsy, Fabry's Disease, Fahr's Syndrome, Fainting, FamilialDysautonomia, Familial Hemangioma, Familial Idiopathic Basal Ganglia,Calcification, Familial Periodic Paralyses, Familial Spastic Paralysis,Febrile Seizures, Fisher Syndrome, Floppy Infant Syndrome, Friedreich'sAtaxia, Frontotemporal, Dementia, Gaucher's Disease, Gerstmann'sSyndrome, Gerstmann-Straussler-Scheinker, Disease, Giant Cell Arteritis,Giant Cell Inclusion Disease, Globoid Cell Leukodystrophy,Glossopharyngeal Neuralgia, Guillain-Barre Syndrome, Hallervorden-SpatzDisease, Head Injury, Headache, Hemicrania Continua, Hemifacial Spasm,Hemiplegia Alterans, Hereditary Neuropathies, Hereditary SpasticParaplegia, Heredopathia Atactica Polyneuritiformis, Herpes Zoster,Herpes Zoster Oticus, Hirayama Syndrome, Holmes-Adie syndrome,Holoprosencephaly, HTLV-1 Associated, Myelopathy, Huntington's Disease,Hydranencephaly, Hydrocephalus, Hydrocephalus-Normal Pressure,Hydromyelia, Hyperactivity, Hypercortisolism, Hypersomnia, Hypertonia,Hypotonia,—Infantile, Hypoxia, Immune-Mediated Encephalomyelitis,Inclusion Body Myositis, Incontinentia Pigmenti, Infantile Hypotonia,Infantile Neuroaxonal Dystrophy, Infantile Phytanic Acid StorageDisease, Infantile Refsum Disease, Infantile Spasms, InflammatoryMyopathy, Iniencephaly, Intestinal Lipodystrophy, Intracranial Cysts,Intracranial Hypertension, Isaac's Syndrome, Joubert Syndrome,Kearns-Sayre Syndrome, Kennedy's Disease, Kinsbourne syndrome,Kleine-Levin Syndrome, Klippel-Feil Syndrome, Klippel-Trenaunay Syndrome(KTS), Klüver-Bucy Syndrome, Korsakoffs Amnesic Syndrome, KrabbeDisease, Kugelberg-Welander Disease, Kuru, Lambert-Eaton MyasthenicSyndrome, Landau-Kleffner Syndrome, Lateral Femoral, Cutaneous NerveEntrapment, Lateral Medullary Syndrome, Learning Disabilities, Leigh'sDisease, Lennox-Gastaut Syndrome, Lesch-Nyhan Syndrome, Leukodystrophy,Levine-Critchley Syndrome, Lewy Body Dementia, Lipid Storage Diseases,Lissencephaly, Locked-In Syndrome, Lou Gehrig's Disease,Lupus—Neurological, Sequelae, Lyme Disease—Neurological Complications,Machado-Joseph Disease, Macrencephaly, Mania, Megalencephaly,Melkersson-Rosenthal Syndrome, Meningitis, Meningitis and Encephalitis,Menkes Disease, Meralgia Paresthetica, Metachromatic, Leukodystrophy,Microcephaly, Migraine, Miller Fisher Syndrome, Mini-Strokes,Mitochondrial Myopathies, Mobius Syndrome, Monomelic Amyotrophy, MotorNeuron Diseases, Moyamoya Disease, Mucolipidoses, Mucopolysaccharidoses,Multifocal Motor Neuropathy, Multi-Infarct Dementia, Multiple Sclerosis,Multiple System Atrophy, Multiple System Atrophy with OrthostaticHypotension, Muscular Dystrophy, Myasthenia-Congenital, MyastheniaGravis, Myelinoclastic Diffuse Sclerosis, Myoclonic Encephalopathy ofInfants, Myoclonus, Myopathy, Myopathy-Congenital, Myopathy-Thyrotoxic,Myotonia, Myotonia Congenita, Narcolepsy, Neuroacanthocytosis,Neurodegeneration with Brain Iron Accumulation, Neurofibromatosis,Neuroleptic Malignant Syndrome, Neurological Complications of AIDS,Neurological Complications Of Lyme Disease, Neurological Consequences ofCytomegalovirus Infection, Neurological Manifestations of Pompe Disease,Neurological Sequelae Of Lupus, Neuromyelitis Optica, Neuromyotonia,Neuronal Ceroid, Lipofuscinosis, Neuronal Migration Disorders,Neuropathy-Hereditary, Neurosarcoidosis, Neurotoxicity, NevusCavernosus, Niemann-Pick Disease, Normal Pressure Hydrocephalus,Occipital Neuralgia, Obesity, Occult Spinal Dysraphism Sequence,Ohtahara Syndrome, Olivopontocerebellar Atrophy, Opsoclonus Myoclonus,Orthostatic Hypotension, O'Sullivan-McLeod Syndrome, Overuse Syndrome,Pain-Chronic, Paine, Pantothenate Kinase-Associated Neurodegeneration,Paraneoplastic Syndromes, Paresthesia, Parkinson's Disease, ParoxysmalChoreoathetosis, Paroxysmal Hemicrania, Parry-Romberg,Pelizaeus-Merzbacher Disease, Pena Shokeir II Syndrome, PerineuralCysts, Periodic Paralyses, Peripheral Neuropathy, PeriventricularLeukomalacia, Persistent Vegetative State, Pervasive DevelopmentalDisorders, Phytanic Acid Storage Disease, Pick's Disease, Pinched Nerve,Piriformis Syndrome, Pituitary Tumors, Polymyositis, Pompe Disease,Porencephaly, Postherpetic Neuralgia, Postinfectious Encephalomyelitis,Post-Polio Syndrome, Postural Hypotension, Postural Orthostatic,Tachycardia Syndrome, Postural Tachycardia Syndrome, Primary DentatumAtrophy, Primary Lateral Sclerosis, Primary Progressive Aphasia, PrionDiseases, Progressive Hemifacial Atrophy, Progressive Locomotor Ataxia,Progressive Multifocal, Leukoencephalopathy, Progressive SclerosingPoliodystrophy, Progressive Supranuclear, Palsy, Prosopagnosia,Pseudotumor Cerebri, Ramsay Hunt Syndrome I (formerly known as), RamsayHunt Syndrome II (formerly known as), Rasmussen's Encephalitis, ReflexSympathetic Dystrophy Syndrome, Refsum Disease, RefsumDisease-Infantile, Repetitive Motion Disorders, Repetitive StressInjuries, Restless Legs Syndrome, Retrovirus-Associated Myelopathy, RettSyndrome, Reye's Syndrome, Riley-Day Syndrome, Sacral Nerve Root Cysts,Saint Vitus Dance, Salivary Gland Disease, Sandhoff Disease, Schilder'sDisease, Schizencephaly, Seitelberger Disease, Seizure Disorder,Semantic Dementia, Septo-Optic Dysplasia, Shaken Baby Syndrome, ShinglesShy-Drager Syndrome, Sjogren's Syndrome, Sleep Apnea, Sleeping Sickness,Sotos Syndrome, Spasticity, Spina Bifida, Spinal Cord Infarction, SpinalCord Injury, Spinal Cord Tumors, Spinal Muscular Atrophy,Spinocerebellar Atrophy, Spinocerebellar, Degeneration,Steele-Richardson-Olszewski Syndrome, Stiff-Person Syndrome,Striatonigral Degeneration, Stroke, Sturge-Weber Syndrome, SubacuteSclerosing Panencephalitis, Subcortical Arteriosclerotic Encephalopathy,SUNCT Headache Swallowing Disorders, Sydenham Chorea, Syncope,Syphilitic Spinal Sclerosis, Syringohydromyelia, Syringomyelia, SystemicLupus Erythematosus, Tabes Dorsalis Tardive Dyskinesia, Tarlov Cysts,Tay-Sachs Disease, Temporal Arteritis, Tethered Spinal Cord Syndrome,Thomsen's Myotonia, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, TicDouloureux, Todd's Paralysis, Tourette Syndrome, Transient IschemicAttack, Transmissible Spongiform Encephalopathies, Transverse Myelitis,Traumatic Brain Injury, Tremor, Trigeminal Neuralgia, Tropical SpasticParaparesis, Tuberous Sclerosis, Vascular Erectile Tumor, Vasculitisincluding Temporal Arteritis, Von Economo's Disease, Von Hippel-LindauDisease (VHL), Von Recklinghausen's Disease, Wallenberg's Syndrome,Werdnig-Hoffman Disease, Wernicke-Korsakoff Syndrome, West Syndrome,Whiplash, Whipple's Disease, Williams Syndrome, Wilson's Disease,X-Linked Spinal and Bulbar Muscular Atrophy, or Zellweger Syndrome.

The term “bioactive agent” is used to describe an agent, other than acompound according to the present disclosure, which is used incombination with the compounds of the present disclosure as an agentwith biological activity to assist in effecting an intended therapy,inhibition and/or prevention/prophylaxis for which the present compoundsare used.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastic juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts, among numerousother acids and bases well known in the pharmaceutical art. Sodium andpotassium salts are particularly preferred as neutralization salts ofthe phosphates according to the present disclosure.

The term “pharmaceutically acceptable derivative” is used throughout thespecification to describe any pharmaceutically acceptable prodrug form(such as an ester, amide other prodrug group), which, uponadministration to a patient, provides directly or indirectly the presentcompound or an active metabolite of the present compound.

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “hydrocarbyl” shall mean a compound which contains carbon andhydrogen and which may be fully saturated, partially unsaturated oraromatic and includes aryl groups, alkyl groups, alkenyl groups andalkynyl groups.

The term “alkyl” shall mean within its context a linear, branch-chainedor cyclic fully saturated hydrocarbon radical or alkyl group, preferablya C₁-C₁₀, more preferably a C₁-C₆, alternatively a C₁-C₃ alkyl group,which may be optionally substituted. Examples of alkyl groups aremethyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl andcyclohexyl, among others.

The term “lower alkyl” means the alkyl groups with no more than sixcarbon atoms.

The term “unsubstituted” shall mean substituted only with hydrogenatoms. A range of carbon atoms which includes C₀ means that carbon isabsent and is replaced with H. Thus, a range of carbon atoms which isC₀-C₆ includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for C₀, H standsin place of carbon. The term “substituted” or “optionally substituted”shall mean independently (i.e., where more than substituent occurs, eachsubstituent is independent of another substituent) one or moresubstituents (independently up to five substitutents, preferably up tothree substituents, often 1 or 2 substituents on a moiety in a compoundaccording to the present disclosure and may include substituents whichthemselves may be further substituted) at a carbon (or nitrogen)position anywhere on a molecule within context, and includes assubstituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO₂),halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl,especially a methyl group such as a trifluoromethyl), an alkyl group(preferably, C₁-C₁₀, more preferably, C₁-C₆), aryl (especially phenyland substituted phenyl for example benzyl or benzoyl), alkoxy group(preferably, C₁-C₆ alkyl or aryl, including phenyl and substitutedphenyl), thioether (C₁-C₆ alkyl or aryl), acyl (preferably, C₁-C₆ acyl),ester or thioester (preferably, C₁-C₆ alkyl or aryl) including alkyleneester (such that attachment is on the alkylene group, rather than at theester function which is preferably substituted with a C₁-C₆ alkyl oraryl group), preferably, C₁-C₆ alkyl or aryl, halogen (preferably, F orCl), amine (including a five- or six-membered cyclic alkylene amine,further including a C₁-C₆ alkyl amine or a C₁-C₆ dialkyl amine whichalkyl groups may be substituted with one or two hydroxyl groups) or anoptionally substituted —N(C₀-C₆ alkyl)C(O)(O—C₁-C₆ alkyl) group (whichmay be optionally substituted with a polyethylene glycol chain to whichis further bound an alkyl group containing a single halogen, preferablychlorine substituent), hydrazine, amido, which is preferably substitutedwith one or two C₁-C₆ alkyl groups (including a carboxamide which isoptionally substituted with one or two C₁-C₆ alkyl groups), alkanol(preferably, C₁-C₆ alkyl or aryl), or alkanoic acid (preferably, C₁-C₆alkyl or aryl). Substituents according to the present disclosure mayinclude, for example —SiR₁R₂R₃ groups where each of R₁ and R₂ is asotherwise described herein and R₃ is H or a C₁-C₆ alkyl group,preferably R₁, R₂, R₃ in this context is a C₁-C₃ alkyl group (includingan isopropyl or t-butyl group). Each of the above-described groups maybe linked directly to the substituted moiety or alternatively, thesubstituent may be linked to the substituted moiety (preferably in thecase of an aryl or heteroaryl moiety) through an optionally substituted—(CH₂)_(m)— or alternatively an optionally substituted —(OCH₂)_(m)—,—(OCH₂CH₂)_(m) or —(CH₂CH₂O)_(m)— group, which may be substituted withany one or more of the above-described substituents. Alkylene groups—(CH₂)_(m)— or —(CH₂)_(n)— groups or other chains such as ethyleneglycol chains, as identified above, may be substituted anywhere on thechain. Preferred substitutents on alkylene groups include halogen orC₁-C₆ (preferably C₁-C₃) alkyl groups, which may be optionallysubstituted with one or two hydroxyl groups, one or two ether groups(O—C₁-C₆ groups), up to three halo groups (preferably F), or a sideshainof an amino acid as otherwise described herein and optionallysubstituted amide (preferably carboxamide substituted as describedabove) or urethane groups (often with one or two C₀-C₆ alkylsubstitutents, which group(s) may be further substituted). In certainembodiments, the alkylene group (often a single methylene group) issubstituted with one or two optionally substituted C₁-C₆ alkyl groups,preferably C₁-C₄ alkyl group, most often methyl or O-methyl groups or asidechain of an amino acid as otherwise described herein. In the presentdisclosure, a moiety in a molecule may be optionally substituted with upto five substituents, preferably up to three substituents. Most often,in the present disclosure moieties which are substituted are substitutedwith one or two substituents.

The term “substituted” (each substituent being independent of any othersubstituent) shall also mean within its context of use C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, amido, carboxamido, sulfone, includingsulfonamide, keto, carboxy, C₁-C₆ ester (oxyester or carbonylester),C₁-C₆ keto, urethane —O—C(O)—NR₁R₂ or —N(R₁)—C(O)—O—R₁, nitro, cyano andamine (especially including a C₁-C₆alkylene-NR₁R₂, a mono- or di-C₁-C₆alkyl substituted amines which may be optionally substituted with one ortwo hydroxyl groups). Each of these groups contain unless otherwiseindicated, within context, between 1 and 6 carbon atoms. In certainembodiments, preferred substituents will include for example, —NH—,—NHC(O)—, —O—, ═O, —(CH₂)_(m) (here, m and n are in context, 1, 2, 3, 4,5 or 6), —S—, —S(O)—, SO₂— or —NH—C(O)—NH—, —(CH₂)_(n)OH, —(CH₂)_(n)SH,—(CH₂)_(n)COOH, C₁-C₆ alkyl, —(CH₂)_(n)O—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)—(C₁-C₆ alkyl), —(CH₂)_(n)OC(O)—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)O—(C₁-C₆ alkyl), —(CH₂)_(n)NHC(O)—R₁,—(CH₂)_(n)C(O)—NR₁R₂, —(OCH₂)_(n)OH, —(CH₂O)_(n)COOH, C₁-C₆ alkyl,—(OCH₂)_(n)O—(C₁-C₆ alkyl), —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),—(OCH₂)_(n)NHC(O)—R₁, —(CH₂O)_(n)C(O)—NR₁R₂, —S(O)₂—R_(S), —S(O)—R_(S)(R_(S) is C₁-C₆ alkyl or a —(CH₂)_(m)—NR₁R₂ group), NO₂, CN or halogen(F, Cl, Br, I, preferably F or Cl), depending on the context of the useof the substituent. R₁ and R₂ are each, within context, H or a C₁-C₆alkyl group (which may be optionally substituted with one or twohydroxyl groups or up to three halogen groups, preferably fluorine). Theterm “substituted” shall also mean, within the chemical context of thecompound defined and substituent used, an optionally substituted aryl orheteroaryl group or an optionally substituted heterocyclic group asotherwise described herein. Alkylene groups may also be substituted asotherwise disclosed herein, preferably with optionally substituted C₁-C₆alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl ispreferred, thus providing a chiral center), a sidechain of an amino acidgroup as otherwise described herein, an amido group as describedhereinabove, or a urethane group O—C(O)—NR₁R₂ group where R₁ and R₂ areas otherwise described herein, although numerous other groups may alsobe used as substituents. Various optionally substituted moieties may besubstituted with 3 or more substituents, preferably no more than 3substituents and preferably with 1 or 2 substituents. It is noted thatin instances where, in a compound at a particular position of themolecule substitution is required (principally, because of valency), butno substitution is indicated, then that substituent is construed orunderstood to be H, unless the context of the substitution suggestsotherwise.

The term “aryl” or “aromatic”, in context, refers to a substituted (asotherwise described herein) or unsubstituted monovalent aromatic radicalhaving a single ring (e.g., benzene, phenyl, benzyl) or condensed rings(e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound tothe compound according to the present disclosure at any available stableposition on the ring(s) or as otherwise indicated in the chemicalstructure presented. Other examples of aryl groups, in context, mayinclude heterocyclic aromatic ring systems “heteroaryl” groups havingone or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic)such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine,pyrimidine, pyrazine, triazole, oxazole or fused ring systems such asindole, quinoline, indolizine, azaindolizine, benzofurazan, etc., amongothers, which may be optionally substituted as described above. Amongthe heteroaryl groups which may be mentioned include nitrogen-containingheteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine,pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine,tetrazole, indole, isoindole, indolizine, azaindolizine, purine,indazole, quinoline, dihydroquinoline, tetrahydroquinoline,isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine,acridine, phenanthridine, carbazole, carbazoline, perimidine,phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine,pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromaticheterocycles such as thiophene and benzothiophene; oxygen-containingaromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuranand isobenzofuran; and aromatic heterocycles comprising 2 or more heteroatoms selected from among nitrogen, sulfur and oxygen, such as thiazole,thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole, among others, all of whichmay be optionally substituted.

The term “heterocycle” refers to a cyclic group which contains at leastone heteroatom, i.e., O, N or S, and may be aromatic (heteroaryl) ornon-aromatic. Thus, the heteroaryl moieties are subsumed under thedefinition of heterocycle, depending on the context of its use.Exemplary heteroaryl groups are described hereinabove. Exemplarynon-aromatic heterocyclic groups for use in the present disclosureinclude, for example, pyrrolidinyl, pyrrolinyl, piperidinyl,piperazinyl, N-methylpiperazinyl, pyrazolidinyl, imidazolidinyl,morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl,pyridone, 2-pyrrolidone, ethyleneurea, 1,3-dioxolane, 1,3-dioxane,1,4-dioxane, phthalimide and succinimide, among others, as describedherein.

The term “co-administration” or “combination therapy” shall mean that atleast two compounds or compositions are administered to the patient atthe same time, such that effective amounts or concentrations of each ofthe two or more compounds may be found in the patient at a given pointin time. Although compounds according to the present disclosure may beco-administered to a patient at the same time, the term embraces bothadministration of two or more agents at the same time or at differenttimes, provided that effective concentrations of all co-administeredcompounds or compositions are found in the subject at a given time. Incertain preferred aspects of the present disclosure, one or more of thepresent compounds described above, are coadministered in combinationwith at least one additional bioactive agent, especially including ananticancer agent. In particularly aspects of the disclosure, theco-administration of compounds results in synergistic therapeutic,including anticancer therapy

The present disclosure describes bifunctional compounds which functionto recruit endogenous proteins to an E3 ubiquitin ligase fordegradation, and methods of using the same. In particular, the presentdisclosure provides bifunctional or proteolysis targeting chimeric(PROTAC) compounds, which find utility as modulators of targetedubiquitination of Tau proteins. An advantage of the compounds providedherein is that a broad range of pharmacological activities is possible,consistent with the degradation/inhibition of Tau protein.

As such, the present disclosure provides such compounds and compositionscomprising an E3 ubiquitin ligase targeting moiety (“ULM”) coupled to aTau protein target binding moiety (“PTM”), which result in theubiquitination of Tau protein, which leads to degradation (and/orinhibition) of the Tau protein. The present disclosure also provides alibrary of compositions and the use thereof.

The present description provides compounds which comprise a ligand,e.g., a small molecule ligand (i.e., having a molecular weight of below2,000, 1,000, 500, or 200 Daltons), which is capable of binding to aubiquitin ligase, such as VHL or cereblon. The compounds also comprise amoiety that is capable of binding to target protein, in such a way thatthe target protein is placed in proximity to the ubiquitin ligase toeffect degradation (and/or inhibition) of that protein. Small moleculecan mean, in addition to the above, that the molecule is non-peptidyl,that is, it is not generally considered a peptide, e.g., comprises fewerthan 4, 3, or 2 amino acids. In accordance with the present description,the PTM, ULM or PROTAC molecule can be a small molecule.

In one embodiment, the description provides a composition useful forregulating protein activity. The composition comprises a ubiquitinpathway protein binding moiety (preferably for VHL or cereblon)according to a defined chemical structure and a Tau protein targetingmoiety which are linked together, preferably through a linker, whereinthe ubiquitin pathway protein binding moiety recognizes a ubiquitinpathway protein and the targeting moiety recognizes Tau target proteinand wherein the ubiquitin pathway protein binding moiety is coupled tothe Tau targeting moiety.

In another embodiment, the present disclosure provides a library ofcompounds. The library comprises more than one compound wherein eachcomposition has a ubiquitin pathway protein binding moiety (preferably,VHL or cereblon) and a Tau protein binding moiety, wherein ULM iscoupled (preferably, through a linker moiety) to Tau, and wherein theubiquitin pathway protein binding moiety recognizes an ubiquitin pathwayprotein, in particular, an E3 ubiquitin ligase.

In another embodiment, the present disclosure provides a method ofubiquitinating/degrading a target protein (e.g. Tau) in a cell. Themethod comprises administering a bifunctional composition comprising anubiquitin pathway protein binding moiety and a targeting moiety,preferably linked through a linker moiety, as otherwise describedherein, wherein the ubiquitin pathway protein binding moiety is coupledto the targeting moiety and wherein the ubiquitin pathway proteinbinding moiety recognizes a ubiquitin pathway protein (e.g., VHL,cereblon) and the targeting moiety recognizes the target protein (e.g.,Tau) such that degradation of the target protein will occur when thetarget protein is placed in proximity to the ubiquitin ligase, thusresulting in degradation/inhibition of the effects of the target proteinand the control of protein levels. The control of protein levelsafforded by the present disclosure provides treatment of a disease stateor condition, which is modulated through the target protein by loweringthe level of that protein in the cells of a patient.

In yet another embodiment, the present disclosure is directed to amethod of treating a patient in need for a disease state or conditionmodulated through a protein (e.g., Tau) where the degradation of thatprotein will produce a therapeutic effect in that patient, the methodcomprising administering to a patient in need an effective amount of acompound according to the present disclosure, optionally in combinationwith another bioactive agent. The disease state or condition may be adisease caused by a microbial agent or other exogenous agent such as avirus, bacteria, fungus, protozoa or other microbe or may be a diseasestate, which is caused by overexpression of a protein i.e. accumulationor aggregation of Tau protein, which leads to a disease state and/orcondition.

In one aspect, the present disclosure provides compounds useful forregulating protein activity. The composition comprises an E3 ubiquitinligase, a ubiquitin pathway protein binding moiety, and a proteintargeting moiety which are linked or coupled together, preferablythrough a linker, wherein the ubiquitin pathway protein binding moietyrecognizes a ubiquitin pathway protein and the targeting moietyrecognizes a target protein (e.g., Tau). Such compounds may be referredto herein as PROTAC compounds or PROTACs with the following generalchemical structure:

ULM-L-PTM,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer,solvate, polymorph or prodrug thereof,

wherein ULM is a small molecule E3 ubiquitin ligase binding moiety thatbinds an E3 ubiquitin ligase;

PTM is a small molecule comprising a Tau protein targeting moiety thatdegrades the Tau protein; and

L is a bond or a chemical linking moiety connecting ULM and PTM.

In certain embodiments, the E3 ubiquitin ligase binding moiety targets amember of the group consisting of Von Hippel-Lindau (VLM), cereblon(CLM), mouse double-minute homolog2 (MLM), and IAP (ILM).

In one aspect, the description provides Tau protein binding moieties(PTM). In certain embodiments, PTM is represented by Formula I, FormulaII, Formula III, Formula IV, Formula V, Formula VI, Formula, VII,Formula, VIII, Formula IX, Formula X, or Formula XI:

wherein:

-   -   A, B, C, D, E, and F are independently selected from an        optionally substituted 5- or 6-membered aryl or heteroaryl ring,        an optionally substituted 4- to 7-membered cycloalkyl or a        heterocycloalkyl, where contact between circles indicates ring        fusion; and    -   L_(PTM) is selected from a bond, an alkyl, an alkenyl or an        alkynyl, optionally interrupted by one or more rings (i.e.,        cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or        more functional groups selected from the groups —O—, —S—, —NR¹        _(PTM)— (where R¹ _(PTM) is selected from H or alkyl), —N═N—,        —S(O)—, —SO₂—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO₂—, —NHC(O)NH—,        —NHC(O)O—, or —OC(O)NH—, wherein the said functional group are        optionally located at either end of the linker.

In certain embodiments, aryl and heteroaryl rings of A, B, C, D, E, andF of PTM are optionally substituted with 1-3 substituents eachindependently selected from alkyl, alkenyl, haloalkyl, halogen,hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino,acylamino, trifluoromethyl, and cyano, wherein the said alkyl andalkenyl groups are further optionally substituted.

In certain embodiments, the rings of at least one of A, B, C, F, or acombination thereof is selected from optionally substituted 5- or6-membered aryl or heteroaryl rings;

In certain embodiments, the PTM has the chemical structure of Formula I,wherein:

-   -   A, B and C rings are independently 5- or 6-membered fused aryl        or heteroaryl rings;    -   L_(PTM) is selected from a bond or an alkyl, and    -   D is selected from a 6-membered aryl, heteroaryl or        heterocycloalkyl,    -   wherein A, B, C and D are optionally substituted with alkyl,        haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino,        dialkylamino or cyano.

In certain additional embodiments, The PTM has the chemical structure ofFormula I, wherein:

-   -   A and C are a phenyl or a 6-membered heteroaryl ring;    -   B is a 5-membered heteroaryl ring;    -   L_(PTM) is a bond; and    -   D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl        ring;    -   wherein each A, B, C and D is optionally independently        substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy,        amino, dialkylamino or cyano, and wherein a nitrogen atom of any        of the A, B, C and D rings is not directly connected to a        heteroatom or to a carbon atom, to which another heteroatom is        directly attached.

In other embodiments, the PTM has the chemical structure of Formula IIIor IV, wherein A, B and C are 5- or 6-membered fused aryl or heteroarylrings, L_(PTM) is selected from a bond or an alkyl, and D and E are 5-or 6-membered fused aryl or heteroaryl rings, wherein A, B, C, D and Eare optionally substituted with alkyl, haloalkyl, halogen, hydroxyl,alkoxy, amino, alkylamino, dialkylamino or cyano.

In certain embodiments, the PTM is represented by following chemicalstructure:

wherein:

-   -   R¹, R² and R³ are independently selected from H, methyl, ethyl,        2-fluoroethyl and 2,2,2-trifluoroethyl;    -   R⁴ and R⁵ are independently selected from H, methyl, ethyl and        halogen; and    -   R⁶ is 1 to 2 substituents independently selected from H, methyl,        ethyl and halogen, wherein the PTM is coupled to a ULM via L.

In any of the aspects or embodiments described herein, the PTM iscovalently coupled to one or more ULM (VLM or CLM) groups, or a linkerto which is attached one or more ULM (VLM or CLM) groups as describedherein.

In certain embodiments, PTM is represented by chemical structure:

wherein:

-   -   R¹, R² and R³ are independently selected from H, optionally        substituted alkyl, methyl, ethyl, 2-fluoroethyl and        2,2,2-trifluoroethyl; and    -   R⁷, R⁸, R⁹ and R¹⁰ are 1 to 8 substituents independently        selected from H, optionally substituted alkyl, haloalkyl,        halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino,        trifluoromethyl or cyano, and wherein the PTM is coupled to a        ULM (VLM or CLM) via L.

In certain additional embodiments, PTM is represented by chemicalstructure:

In certain embodiments linker attachment point to PTM is as indicated bythe dotted line:

Exemplary VLMs:

In one aspect ULM is VHL.

In certain embodiments of the compounds as described herein, ULM is VLMand comprises a chemical structure selected from the group ULM-a:

wherein:

-   -   where a dashed line indicates the attachment of at least one        PTM, another ULM or VLM or CLM (i.e., ULM′ or VLM′ or CLM′), or        a chemical linker moiety coupling at least one PTM, a ULM′ or        VLM′ or CLM′ to the other end of the linker;    -   X¹, X² are each independently selected from the group of a bond,        O, NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and SO₂;    -   R^(Y3), R^(Y4) are each independently selected from the group of        H, linear or branched C₁₋₆ alkyl, optionally substituted by 1 or        more halo, C₁₋₆ alkoxyl);    -   R^(P) is 1, 2, or 3 groups, each independently selected from the        group H, halo, —OH, C₁₋₃ alkyl;    -   W³ is selected from the group of an optionally substituted        -T-N(R^(1a)R^(1b)), an optionally substituted        -T-N(R^(1a)R^(1b))X³, -T-Aryl, an optionally substituted        -T-Heteroaryl, an optionally substituted -T-Heterocycle, an        optionally substituted —NR¹-T-Aryl, an optionally substituted        —NR¹-T-Heteroaryl or an optionally substituted        —NR¹-T-Heterocycle;    -   X3 is C═O, R¹, R^(1a), R^(1b)    -   R¹, R^(1a), R^(1b) are each independently selected from the        group consisting of H, linear or branched C₁-C₆ alkyl group        optionally substituted by 1 or more halo or —OH groups,        R^(Y3)C═O, R^(Y3)C═S, R^(Y3)SO, R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O,        N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO, and N(R^(Y3)R^(Y4))SO₂;    -   where T is covalently bonded to X1;    -   W⁴ is an optionally substituted —NR1-T-Aryl, an optionally        substituted —NR1-T-Heteroaryl group or an optionally substituted        —NR1-T-Heterocycle, where —NR1 is covalently bonded to X2 and R1        is H or CH₃, preferably H.

In any of the embodiments described herein, T is selected from the groupof an optionally substituted alkyl, —(CH₂)_(n)— group, wherein each oneof the methylene groups is optionally substituted with one or twosubstituents selected from the group of halogen, methyl, a linear orbranched C₁-C₆ alkyl group optionally substituted by 1 or more halogenor —OH groups or an amino acid side chain optionally substituted; and

-   -   n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.

In certain embodiments, W⁴ is

wherein R_(14a), R_(14b), are each independently selected from the groupof H, haloalkyl, or optionally substituted alkyl;

In any of the aspects or embodiments described herein, W⁵ is selectedfrom the group of a phenyl or a 5-10 membered heteroaryl,

R₁₅ is selected from the group of H, halogen, CN, OH, NO₂,NR_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionally substituted alkyl,optionally substituted haloalkyl, optionally substituted haloalkoxy;aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl;

In additional embodiments, W⁴ substituents for use in the presentdisclosure also include specifically (and without limitation to thespecific compound disclosed) the W⁴ substituents which are found in theidentified compounds disclosed herein. Each of these W⁴ substituents maybe used in conjunction with any number of W³ substituents which are alsodisclosed herein.

In certain additional embodiments, ULM-a, is optionally substituted by1-3 R^(P) groups in the pyrrolidine moiety. Each R^(P) is independentlyH, halo, —OH, C₁₋₃alkyl.

In any of the embodiments described herein, the W³, W⁴ can independentlybe covalently coupled to a linker which is attached one or more PTMgroups.

and wherein the dashed line indicates the site of attachment of at leastone PTM, another ULM (ULM′) or a chemical linker moiety coupling atleast one PTM or a ULM′ or both to ULM.

In certain embodiments, ULM is VHL and is represented by the structure:

wherein:

-   -   W³ is selected from the group of an optionally substituted aryl,        optionally substituted heteroaryl, or

-   -   R₉ and R₁₀ are independently hydrogen, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl,        or R₉, R₁₀, and the carbon atom to which they are attached form        an optionally substituted cycloalkyl;    -   R₁₁ is selected from the group of an optionally substituted        heterocyclic, optionally substituted alkoxy, optionally        substituted heteroaryl, optionally substituted aryl,

-   -   R₁₂ is selected from the group of H or optionally substituted        alkyl;    -   R₁₃ is selected from the group of H, optionally substituted        alkyl, optionally substituted alkylcarbonyl, optionally        substituted (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl;    -   R_(14a), R_(14b), are each independently selected from the group        of H, haloalkyl, or optionally substituted alkyl;    -   W⁵ is selected from the group of a phenyl or a 5-10 membered        heteroaryl,    -   R₁₅ is selected from the group of H, halogen, CN, OH, NO₂, N        R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),        SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionally substituted        alkyl, optionally substituted haloalkyl, optionally substituted        haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl        (each independently optionally substituted);    -   R₁₆ is independently selected from the group of H, halo,        optionally substituted alkyl, optionally substituted haloalkyl,        hydroxy, or optionally substituted haloalkoxy;    -   o is 0, 1, 2, 3, or 4;    -   R₁₈ is independently selected from the group of halo, optionally        substituted alkoxy, cyano, optionally substituted alkyl,        haloalkyl, haloalkoxy or a linker; and    -   p is 0, 1, 2, 3, or 4, and wherein the dashed line indicates the        site of attachment of at least one PTM, another ULM (ULM′) or a        chemical linker moiety coupling at least one PTM or a ULM′ or        both to ULM.

In certain embodiments, R₁₅ is

wherein R₁₇ is H, halo, optionally substituted C₃₋₆cycloalkyl,optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆alkenyl,and C₁₋₆haloalkyl; and Xa is S or O.

In certain embodiments, R₁₇ is selected from the group methyl, ethyl,isopropyl, and cyclopropyl.

In certain additional embodiments, R₁₅ is selected from the groupconsisting of:

In certain embodiments, R₁₁ is selected from the group consisting of:

In certain embodiments, ULM has a chemical structure selected from thegroup of:

wherein:

-   -   R₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted        alkyl, optionally substituted hydroxyalkyl, optionally        substituted heteroaryl, or haloalkyl;    -   R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,        fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R₁₅ is selected from the group consisting of H, halogen, CN, OH,        NO₂, optionally substituted heteroaryl, optionally substituted        aryl; optionally substituted alkyl, optionally substituted        haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or        cycloheteroalkyl;    -   X is C, CH₂, or C═O    -   R₃ is a bond or an optionally substituted 5 or 6 membered        heteroaryl; and    -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM (ULM-a).

In certain embodiments, ULM comprises a group according to the chemicalstructure:

wherein:

-   -   R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,        fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R⁹ is H;    -   R₁₀ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, or cyclohexyl;    -   R11 is

-   -   or optionally substituted heteroaryl;    -   p is 0, 1, 2, 3, or 4;    -   each R₁₈ is independently halo, optionally substituted alkoxy,        cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a        linker;    -   R12 is H, C═O;    -   R13 is H, optionally substituted alkyl, optionally substituted        alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl,        optionally substituted aralkylcarbonyl, optionally substituted        arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or        optionally substituted aralkyl,    -   R₁₅ is selected from the group consisting of H, halogen, Cl, CN,        OH, NO₂, optionally substituted heteroaryl, optionally        substituted aryl;

-   -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM.

In certain embodiments, the ULM is selected from the followingstructures:

-   -   where n is 0 or 1.

In certain embodiments, the ULM is selected from the followingstructures:

wherein the phenyl ring in ULM-a1 through ULM-a15, ULM-b1 throughULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 is optionallysubstituted with fluorine, lower alkyl and alkoxy groups, and whereinthe dashed line indicates the site of attachment of at least one PTM,another ULM (ULM′) or a chemical linker moiety coupling at least one PTMor a ULM′ or both to ULM-a.

In one embodiment, the phenyl ring in ULM-a1 through ULM-a15, ULM-b1through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 can befunctionalized as the ester to make it a part of the prodrug.

In certain embodiments, the hydroxyl group on the pyrrolidine ring ofULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15and ULM-d1 through ULM-d9, respectively, comprises an ester-linkedprodrug moiety.

In any of the aspects or embodiments described herein, the ULM and wherepresent, ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   R^(1′) of ULM-g is an optionally substituted C₁-C₆ alkyl group,        an optionally substituted —(CH₂)_(n)OH, an optionally        substituted —(CH₂)_(n)SH, an optionally substituted        (CH₂)_(n)—O—(C₁-C₆)alkyl group, an optionally substituted        (CH₂)_(n)—WCOCW—(C₀-C₆)alkyl group containing an epoxide moiety        WCOCW where each W is independently H or a C₁-C₃ alkyl group, an        optionally substituted —(CH₂)_(n)COOH, an optionally substituted        —(CH₂)C(O)—(C₁-C₆ alkyl), an optionally substituted        —(CH₂)_(n)NHC(O)—R₁, an optionally substituted        —(CH₂)_(n)C(O)—NR₁R₂, an optionally substituted        —(CH₂)_(n)OC(O)—NR₁R₂, —(CH₂O)_(n)H, an optionally substituted        —(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), an optionally substituted        —(CH₂)C(O)—O—(C₁-C₆ alkyl), an optionally substituted        —(CH₂O)_(n)COOH, an optionally substituted —(OCH₂)_(n)O—(C₁-C₆        alkyl), an optionally substituted —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),        an optionally substituted —(OCH₂)_(n)NHC(O)—R₁, an optionally        substituted —(CH₂O)_(n)C(O)—NR₁R₂, —(CH₂CH₂O)_(n)H, an        optionally substituted —(CH₂CH₂O)_(n)COOH, an optionally        substituted —(OCH₂CH₂)_(n)O—(C₁-C₆ alkyl), an optionally        substituted —(CH₂CH₂O)_(n)C(O)—(C₁-C₆ alkyl), an optionally        substituted —(OCH₂CH₂)_(n)NHC(O)—R₁, an optionally substituted        —(CH₂CH₂O)_(n)C(O)—NR₁R₂, an optionally substituted —SO₂R_(S),        an optionally substituted S(O)R_(S), NO₂, CN or halogen (F, Cl,        Br, I, preferably F or Cl);    -   R₁ and R₂ of ULM-g are each independently H or a C₁-C₆ alkyl        group which may be optionally substituted with one or two        hydroxyl groups or up to three halogen groups (preferably        fluorine);    -   R_(S) of ULM-g is a C₁-C₆ alkyl group, an optionally substituted        aryl, heteroaryl or heterocycle group or a —(CH₂)_(m)NR₁R₂        group;    -   X and X′ of ULM-g are each independently C═O, C═S, —S(O), S(O)₂,        (preferably X and X′ are both C═O);    -   R^(2′) of ULM-g is an optionally substituted        —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)alkyl group, an optionally        substituted —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)NR_(1N)R_(2N)        group, an optionally substituted        —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl,        an optionally substituted        —(CH₂)_(n)—(C═O)_(v)NR₁(SO₂)_(w)-Heterocycle, an optionally        substituted —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)— NR_(1N)R_(2N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —NR¹—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted        —NR¹—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl or an        optionally substituted        —NR¹—(CH₂)_(n)—(C═O)_(v)NR₁(SO₂)_(w)-Heterocycle, an optionally        substituted —X^(R2′)-alkyl group; an optionally substituted        —X^(R2′)— Aryl group; an optionally substituted —X^(R2′)—        Heteroaryl group; an optionally substituted —X^(R2′)—        Heterocycle group; an optionally substituted;    -   R^(3′) of ULM-g is an optionally substituted alkyl, an        optionally substituted        —(CH₂)_(n)—(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N),        an optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—C(O)NR₁R₂, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an        optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle,        an optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—        NR_(1N)R_(2N), an optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle, an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(W)—NR_(1N)R_(2N), an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl        or an optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle;        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-alkyl group, an        optionally substituted        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Aryl group, an optionally        substituted —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Heteroaryl        group, an optionally substituted        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Heterocycle group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-alkyl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Aryl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Heteroaryl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Heterocycle group, an        optionally substituted —X^(R3′)— alkyl group; an optionally        substituted —X^(R3′)— Aryl group; an optionally substituted        —X^(R3′)— Heteroaryl group; an optionally substituted —X^(R3′)—        Heterocycle group; an optionally substituted;    -   R_(1N) and R_(2N) of ULM-g are each independently H, C₁-C₆ alkyl        which is optionally substituted with one or two hydroxyl groups        and up to three halogen groups or an optionally substituted        —(CH₂)_(n)-Aryl, —(CH₂)_(n)-Heteroaryl or —(CH₂)_(n)-Heterocycle        group;    -   V of ULM-g is O, S or NR₁;    -   R₁ of ULM-g is the same as above;    -   R¹ and R_(1′) of ULM-g are each independently H or a C₁-C₃ alkyl        group;    -   X^(R2′) and X^(R3′) of ULM-g are each independently an        optionally substituted —CH₂)_(n)—,        —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans), —CH₂)_(n)—CH≡CH—,        —(CH₂CH₂O)_(n)— or a C₃-C₆ cycloalkyl group, where X_(v) is H, a        halo or a C₁-C₃ alkyl group which is optionally substituted;    -   each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;    -   each m′ of ULM-g is independently 0 or 1;    -   each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;    -   each n′ of ULM-g is independently 0 or 1;    -   each u of ULM-g is independently 0 or 1;    -   each v of ULM-g is independently 0 or 1;    -   each w of ULM-g is independently 0 or 1; and    -   any one or more of R^(1′), R^(2′), R^(3′), X and X′ of ULM-g is        optionally modified to be covalently bonded to the PTM group        through a linker group when PTM is not ULM′, or when PTM is        ULM′, any one or more of R^(1′), R^(2′), R^(3′), X and X′ of        each of ULM and ULM′ are optionally modified to be covalently        bonded to each other directly or through a linker group, or a        pharmaceutically acceptable salt, stereoisomer, solvate or        polymorph thereof.

In any of the aspects or embodiments described herein, the ULM and whenpresent, ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   each of R^(1′), R^(2′) and R^(3′) of ULM-h are the same as above        and X is C═O, C═S, —S(O) group or a S(O)₂ group, more preferably        a C═O group, and    -   any one or more of R^(1′), R^(2′) and R^(3′) of ULM-h are        optionally modified to bind a linker group to which is further        covalently bonded to the PTM group when PTM is not ULM′, or when        PTM is ULM′, any one or more of R^(1′), R^(2′), R^(3′) of each        of ULM and ULM′ are optionally modified to be covalently bonded        to each other directly or through a linker group, or    -   a pharmaceutically acceptable salt, enantiomer, diastereomer,        solvate or polymorph thereof.

In any of the aspects or embodiments described herein, the ULM, and whenpresent, ULM′, are each independently according to the chemicalstructure:

wherein:

-   -   any one or more of R^(1′), R^(2′) and R^(3′) of ULM-I are        optionally modified to bind a linker group to which is further        covalently bonded to the PTM group when PTM is not ULM′, or when        PTM is ULM′, any one or more of R^(1′), R^(2′), R^(3′) of each        of ULM and ULM′ are optionally modified to be covalently bonded        to each other directly or through a linker group, or    -   a pharmaceutically acceptable salt, enantiomer, diastereomer,        solvate or polymorph thereof.

In further preferred aspects of the invention, R^(1′) of ULM-g throughULM-i is preferably a hydroxyl group or a group which may be metabolizedto a hydroxyl or carboxylic group, such that the compound represents aprodrug form of an active compound. Exemplary preferred R^(1′) groupsinclude, for example, —(CH₂)_(n)OH, (CH₂)_(n)—O—(C₁-C₆)alkyl group,—(CH₂)_(n)COOH, —(CH₂O)_(n)H, an optionally substituted—(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), or an optionally substituted—(CH₂)_(n)C(O)—O—(C₁-C₆ alkyl), wherein n is 0 or 1. Where R^(1′) is orcontains a carboxylic acid group, a hydroxyl group or an amine group,the hydroxyl group, carboxylic acid group or amine (each of which may beoptionally substituted), may be further chemically modified to provide acovalent link to a linker group to which the PTM group (including a ULM′group) is bonded;

X and X′, where present, of ULM-g and ULM-h are preferably a C═O, C═S,—S(O) group or a S(O)₂ group, more preferably a C═O group;

R^(2′) of ULM-g through ULM-i is preferably an optionally substituted—NR¹-T-Aryl, an optionally substituted —NR¹-T-Heteroaryl group or anoptionally substituted —NR¹-T-Heterocycle, where R¹ is H or CH₃,preferably H and T is an optionally substituted —(CH₂)_(n)— group,wherein each one of the methylene groups may be optionally substitutedwith one or two substituents, preferably selected from halogen, an aminoacid sidechain as otherwise described herein or a C₁-C₃alkyl group,preferably one or two methyl groups, which may be optionallysubstituted; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1.Alternatively, T may also be a —(CH₂O)_(n)— group, a —(OCH₂)_(n)— group,a —(CH₂CH₂O)_(n)— group, a —(OCH₂CH₂)_(n)— group, all of which groupsare optionally substituted.

Preferred Aryl groups for R^(2′) of ULM-g through ULM-i includeoptionally substituted phenyl or naphthyl groups, preferably phenylgroups, wherein the phenyl or naphthyl group is optionally connected toa PTM group (including a ULM′ group) via a linker group, a halogen(preferably F or Cl), an amine, monoalkyl- or dialkyl amine (preferably,dimethylamine), F, Cl, OH, COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe,OCF₃, NO₂, or CN group (each of which may be substituted in ortho-,meta- and/or para-positions of the phenyl ring, preferably para-), anoptionally substituted phenyl group (the phenyl group itself isoptionally connected to a PTM group (including a ULM′ group) via alinker group), and/or at least one of F, Cl, OH, COOH, CH₃, CF₃, OMe,OCF₃, NO₂, or CN group (in ortho-, meta- and/or para-positions of thephenyl ring, preferably para-), a naphthyl group, which may beoptionally substituted, an optionally substituted heteroaryl, preferablyan optionally substituted isoxazole including a methylsubstitutedisoxazole, an optionally substituted oxazole including amethylsubstituted oxazole, an optionally substituted thiazole includinga methyl substituted thiazole, an optionally substituted isothiazoleincluding a methyl substituted isothiazole, an optionally substitutedpyrrole including a methylsubstituted pyrrole, an optionally substitutedimidazole including a methylimidazole, an optionally substitutedbenzimidazole or methoxybenzylimidazole, an optionally substitutedoximidazole or methyloximidazole, an optionally substituted diazolegroup, including a methyldiazole group, an optionally substitutedtriazole group, including a methylsubstituted triazole group, anoptionally substituted pyridine group, including a halo- (preferably, F)or methylsubstitutedpyridine group or an oxapyridine group (where thepyridine group is linked to the phenyl group by an oxygen), anoptionally substituted furan, an optionally substituted benzofuran, anoptionally substituted dihydrobenzofuran, an optionally substitutedindole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), anoptionally substituted quinoline, an optionally substituted groupaccording to the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl) each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted phenyl group, an optionally substituted heteroaryl,        or an optionally substituted heterocycle, preferably for example        piperidine, morpholine, pyrrolidine, tetrahydrofuran);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2 of ULM-g through ULM-i) are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group; and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1), or an optionally substituted        heterocycle, preferably tetrahydrofuran, tetrahydrothiene,        piperidine, piperazine or morpholine (each of which groups when        substituted, are preferably substituted with a methyl or halo        (F, Br, Cl), each of which groups may be optionally connected to        a PTM group (including a ULM′ group) via a linker group.

In certain preferred aspects,

of ULM-g through ULM-i is a

group,

-   -   where R^(PRO) and n of ULM-g through ULM-i are the same as        above.

Preferred heteroaryl groups for R^(2′) of ULM-g through ULM-i include anoptionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole, an optionally substitutedindolizine, an optionally substituted azaindolizine, an optionallysubstituted benzofuran, including an optionally substituted benzofuran,an optionally substituted isoxazole, an optionally substituted thiazole,an optionally substituted isothiazole, an optionally substitutedthiophene, an optionally substituted pyridine (2-, 3, or 4-pyridine), anoptionally substituted imidazole, an optionally substituted pyrrole, anoptionally substituted diazole, an optionally substituted triazole, atetrazole, an optionally substituted oximidazole, or a group accordingto the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) of ULM-g through ULM-i is H or a C₁-C₆        alkyl group (preferably C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl), each        of which groups may be optionally connected to a PTM group        (including a ULM′ group) via a linker group.

Preferred heterocycle groups for R^(2′) of ULM-g through ULM-i includetetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine,piperazine, pyrrollidine, morpholine, oxane or thiane, each of whichgroups may be optionally substituted, or a group according to thechemical structure:

-   -   preferably, a

group,wherein:

-   -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl, heteroaryl or        heterocyclic group;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (often 0 or 1), each of which groups may be optionally        connected to a PTM group (including a ULM′ group) via a linker        group.

Preferred R^(2′) substituents of ULM-g through ULM-i also includespecifically (and without limitation to the specific compound disclosed)the R^(2′) substituents which are found in the identified compoundsdisclosed herein (which includes the specific compounds which aredisclosed in the present specification, and the FIGURES which areattached hereto). Each of these R^(2′) substituents may be used inconjunction with any number of R^(3′) substituents which are alsodisclosed herein.

R^(3′) of ULM-g through ULM-i is preferably an optionally substituted-T-Aryl, an optionally substituted-T-Heteroaryl, an optionallysubstituted -T-Heterocycle, an optionally substituted-NR¹-T-Aryl, anoptionally substituted —NR¹-T-Heteroaryl or an optionallysubstituted-NR¹-T-Heterocycle, where R¹ is H or a C₁-C₃ alkyl group,preferably H or CH₃, T is an optionally substituted —(CH₂)_(n)— group,wherein each one of the methylene groups may be optionally substitutedwith one or two substituents, preferably selected from halogen, a C₁-C₃alkyl group or the sidechain of an amino acid as otherwise describedherein, preferably methyl, which may be optionally substituted; and n is0 to 6, often 0, 1, 2, or 3 preferably 0 or 1. Alternatively, T may alsobe a —(CH₂O)_(n)— group, a —(OCH₂)_(n)— group, a —(CH₂CH₂O)_(n)— group,a —(OCH₂CH₂)_(n)— group, each of which groups is optionally substituted.

Preferred aryl groups for R^(3′) of ULM-g through ULM-i includeoptionally substituted phenyl or naphthyl groups, preferably phenylgroups, wherein the phenyl or naphthyl group is optionally connected toa PTM group (including a ULM′ group) via a linker group and/or a halogen(preferably F or Cl), an amine, monoalkyl- or dialkyl amine (preferably,dimethylamine), an amido group (preferably a —(CH₂)_(m)—NR₁C(O)R² groupwhere m, R₁ and R₂ are the same as above), a halo (often F or Cl), OH,CH₃, CF₃, OMe, OCF₃, NO₂, CN or a S(O)₂R_(S) group (R_(S) is a a C₁-C₆alkyl group, an optionally substituted aryl, heteroaryl or heterocyclegroup or a —(CH₂)_(m)NR₁R₂ group), each of which may be substituted inortho-, meta- and/or para-positions of the phenyl ring, preferablypara-), or an Aryl (preferably phenyl), Heteroaryl or Heterocycle.Preferably said substituent phenyl group is an optionally substitutedphenyl group (i.e., the substituent phenyl group itself is preferablysubstituted with at least one of F, Cl, OH, SH, COOH, CH₃, CF₃, OMe,OCF₃, NO₂, CN or a linker group to which is attached a PTM group(including a ULM′ group), wherein the substitution occurs in ortho-,meta- and/or para-positions of the phenyl ring, preferably para-), anaphthyl group, which may be optionally substituted including asdescribed above, an optionally substituted heteroaryl (preferably anoptionally substituted isoxazole including a methylsubstitutedisoxazole, an optionally substituted oxazole including amethylsubstituted oxazole, an optionally substituted thiazole includinga methyl substituted thiazole, an optionally substituted pyrroleincluding a methylsubstituted pyrrole, an optionally substitutedimidazole including a methylimidazole, a benzylimidazole ormethoxybenzylimidazole, an oximidazole or methyloximidazole, anoptionally substituted diazole group, including a methyldiazole group,an optionally substituted triazole group, including a methylsubstitutedtriazole group, a pyridine group, including a halo- (preferably, F) ormethylsubstitutedpyridine group or an oxapyridine group (where thepyridine group is linked to the phenyl group by an oxygen) or anoptionally substituted heterocycle (tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine,tetrahydroquinoline, oxane or thiane. Each of the aryl, heteroaryl orheterocyclic groups may be optionally connected to a PTM group(including a ULM′ group) via a linker group.

Preferred Heteroaryl groups for R^(3′) of ULM-g through ULM-i include anoptionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl). Each        of said heteroaryl groups may be optionally connected to a PTM        group (including a ULM′ group) via a linker group.

Preferred heterocycle groups for R³ of ULM-g through ULM-i includetetrahydroquinoline, piperidine, piperazine, pyrrollidine, morpholine,tetrahydrofuran, tetrahydrothiophene, oxane and thiane, each of whichgroups may be optionally substituted or a group according to thechemical structure:

preferably, a

group,wherein:

-   -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group, and    -   each n of ULM-g through ULM-i is 0, 1, 2, 3, 4, 5, or 6        (preferably 0 or 1), wherein each of said Heterocycle groups may        be optionally connected to a PTM group (including a ULM′ group)        via a linker group.

Preferred R^(3′) substituents of ULM-g through ULM-i also includespecifically (and without limitation to the specific compound disclosed)the R^(3′) substituents which are found in the identified compoundsdisclosed herein (which includes the specific compounds which aredisclosed in the present specification, and the FIGURES which areattached hereto). Each of these R^(3′) substituents may be used inconjunction with any number of R^(2′) substituents, which are alsodisclosed herein.

In certain alternative preferred embodiments, R^(2′) of ULM-g throughULM-i is an optionally substituted —NR₁—X^(R2′)-alkyl group,—NR₁—X^(R2′)-Aryl group; an optionally substituted —NR₁— X^(R2′)-HET, anoptionally substituted —NR₁—X^(R2′)-Aryl-HET or an optionallysubstituted —NR₁—X^(R2′)-HET-Aryl,

wherein:

-   -   R₁ of ULM-g through ULM-i is H or a C₁-C₃ alkyl group        (preferably H);    -   X^(R2′) of ULM-g through ULM-i is an optionally substituted        —CH₂)_(n)—, —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans),        —(CH₂)_(n)—CH≡CH—, —(CH₂CH₂O)_(n)— or a C₃-C₆ cycloalkyl group;        and    -   X_(v) of ULM-g through ULM-i is H, a halo or a C₁-C₃ alkyl group        which is optionally substituted with one or two hydroxyl groups        or up to three halogen groups;    -   Alkyl of ULM-g through ULM-i is an optionally substituted C₁-C₁₀        alkyl (preferably a C₁-C₆ alkyl) group (in certain preferred        embodiments, the alkyl group is end-capped with a halo group,        often a Cl or Br);    -   Aryl of ULM-g through ULM-i is an optionally substituted phenyl        or naphthyl group (preferably, a phenyl group); and    -   HET of ULM-g through ULM-i is an optionally substituted oxazole,        isoxazole, thiazole, isothiazole, imidazole, diazole,        oximidazole, pyrrole, pyrollidine, furan, dihydrofuran,        tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene,        pyridine, piperidine, piperazine, morpholine, benzofuran,        indole, indolizine, azaindolizine, quinoline (when substituted,        each preferably substituted with a C₁-C₃ alkyl group, preferably        methyl or a halo group, preferably F or Cl) or a group according        to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group, and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1).

Each of said groups may be optionally connected to a PTM group(including a ULM′ group) via a linker group.

In certain alternative preferred embodiments of the present invention,R^(3′) of ULM-g through ULM-i is an optionally substituted—(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)—R^(S3′) group, an optionallysubstituted-(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)—R^(S3′) group, anoptionally substituted —X^(R3′)-alkyl group, an optionally substituted—X^(R3′)-Aryl group; an optionally substituted —X^(R3′)-HET group, anoptionally substituted —X^(R3′)-Aryl-HET group or an optionallysubstituted —X^(R3′)-HET-Aryl group, wherein:

-   -   R^(S3′) is an optionally substituted alkyl group (C₁-C₁₀,        preferably C₁-C₆ alkyl), an optionally substituted Aryl group or        a HET group;    -   R_(1′) is H or a C₁-C₃ alkyl group (preferably H);    -   V is O, S or NR_(1′);    -   X^(R3′) is —(CH₂)_(n)—, —(CH₂CH₂O)_(n)—,        —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans), —CH₂)_(n)—CH≡CH—,        or a C₃-C₆ cycloalkyl group, all optionally substituted;    -   X_(v) is H, a halo or a C₁-C₃ alkyl group which is optionally        substituted with one or two hydroxyl groups or up to three        halogen groups;    -   Alkyl is an optionally substituted C₁-C₁₀ alkyl (preferably a        C₁-C₆ alkyl) group (in certain preferred embodiments, the alkyl        group is end-capped with a halo group, often a Cl or Br);    -   Aryl is an optionally substituted phenyl or napthyl group        (preferably, a phenyl group); and    -   HET is an optionally substituted oxazole, isoxazole, thiazole,        isothiazole, imidazole, diazole, oximidazole, pyrrole,        pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene,        dihydrothiene, tetrahydrothiene, pyridine, piperidine,        piperazine, morpholine, benzofuran, indole, indolizine,        azaindolizine, quinoline (when substituted, each preferably        substituted with a C₁-C₃ alkyl group, preferably methyl or a        halo group, preferably F or Cl), or a group according to the        chemical structure:

S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;

-   -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1);    -   each m′ of ULM-g through ULM-i is 0 or 1; and    -   each n′ of ULM-g through ULM-i is 0 or 1;    -   wherein each of said compounds, preferably on the alkyl, Aryl or        Het groups, is optionally connected to a PTM group (including a        ULM′ group) via a linker group.

In alternative embodiments, R^(3′) of ULM-g through ULM-i is—(CH₂)_(n)-Aryl, —(CH₂CH₂O)_(n)-Aryl, —(CH₂)_(n)-HET or—(CH₂CH₂O)_(n)-HET,

wherein:

-   -   said Aryl of ULM-g through ULM-i is phenyl which is optionally        substituted with one or two substitutents, wherein said        substituent(s) is preferably selected from —(CH₂)_(n)OH, C₁-C₆        alkyl which itself is further optionally substituted with CN,        halo (up to three halo groups), OH, —(CH₂)_(n)O(C₁-C₆)alkyl,        amine, mono- or di-(C₁-C₆ alkyl) amine wherein the alkyl group        on the amine is optionally substituted with 1 or 2 hydroxyl        groups or up to three halo (preferably F, Cl) groups, or    -   said Aryl group of ULM-g through ULM-i is substituted with        —(CH₂)_(n)OH, —(CH₂)_(n)—O—(C₁-C₆)alkyl,        —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl, —(CH₂)_(n)—C(O)(C₀-C₆)        alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,        —(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl)        amine wherein the alkyl group on the amine is optionally        substituted with 1 or 2 hydroxyl groups or up to three halo        (preferably F, Cl) groups, CN, NO₂, an optionally substituted        —(CH₂)_(n)—(V)_(m′)—CH₂)_(n)—(V)_(m′)—(C₁-C₆)alkyl group, a        —(V)_(m′)—(CH₂CH₂O)_(n)—R^(PEG) group where V is O, S or        NR_(1′), R_(1′) is H or a C₁-C₃ alkyl group (preferably H) and        R^(PEG) is H or a C₁-C₆ alkyl group which is optionally        substituted (including being optionally substituted with a        carboxyl group), or    -   said Aryl group of ULM-g through ULM-i is optionally substituted        with a heterocycle, including a heteroaryl, selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, benzofuran, indole, indolizine, azaindolizine, (when        substituted each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        or a group according to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   HET of ULM-g through ULM-i is preferably oxazole, isoxazole,        thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole,        pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene,        dihydrothiene, tetrahydrothiene, pyridine, piperidine,        piperazine, morpholine, quinoline, (each preferably substituted        with a C₁-C₃ alkyl group, preferably methyl or a halo group,        preferably F or Cl), benzofuran, indole, indolizine,        azaindolizine, or a group according to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl, heteroaryl or        heterocyclic group;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   each m′ of ULM-g through ULM-i is independently 0 or 1; and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1),    -   wherein each of said compounds, preferably on said Aryl or HET        groups, is optionally connected to a PTM group (including a ULM′        group) via a linker group.

In still additional embodiments, preferred compounds include thoseaccording to the chemical structure:

wherein:

-   -   R^(1′) of ULM-i is OH or a group which is metabolized in a        patient or subject to OH;    -   R^(2′) of ULM-i is a —NH—CH₂-Aryl-HET (preferably, a phenyl        linked directly to a methyl substituted thiazole);    -   R^(3′) of ULM-i is a —CHR^(CR3′)—NH—C(O)—R^(3P1) group or a        —CHR^(CR3′)—R^(3P2) group;    -   R^(CR3′) of ULM-i is a C₁-C₄ alkyl group, preferably methyl,        isopropyl or tert-butyl;    -   R^(3P1) of ULM-i is C₁-C₃ alkyl (preferably methyl), an        optionally substituted oxetane group (preferably methyl        substituted, a —(CH₂)_(n)OCH₃ group where n is 1 or 2        (preferably 2), or a

group (the ethyl ether group is preferably meta-substituted on thephenyl moiety), a morpholino group (linked to the carbonyl at the 2- or3-position;

-   -   R^(3P2) of ULM-i is a

group;

-   -   Aryl of ULM-i is phenyl;    -   HET of ULM-i is an optionally substituted thiazole or        isothiazole; and    -   R^(HET) of ULM-i is H or a halo group (preferably H);    -   or a pharmaceutically acceptable salt, stereoisomer, solvate or        polymorph thereof, wherein each of said compounds is optionally        connected to a PTM group (including a ULM′ group) via a linker        group.

In certain aspects, bifunctional compounds comprising a ubiquitin E3ligase binding moiety (ULM), wherein ULM is a group according to thechemical structure:

wherein:

-   -   each R₅ and R₆ of ULM-j is independently OH, SH, or optionally        substituted alkyl or R₅, R₆, and the carbon atom to which they        are attached form a carbonyl;    -   R₇ of ULM-j is H or optionally substituted alkyl;    -   E of ULM-j is a bond, C═O, or C═S;    -   G of ULM-j is a bond, optionally substituted alkyl, —COOH or        C=J;    -   J of ULM-j is O or N—R₈;    -   R₈ of ULM-j is H, CN, optionally substituted alkyl or optionally        substituted alkoxy;    -   M of ULM-j is optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclic or

-   -   each R₉ and R₁₀ of ULM-j is independently H; optionally        substituted alkyl, optionally substituted cycloalkyl, optionally        substituted hydroxyalkyl, optionally substituted thioalkyl, a        disulphide linked ULM, optionally substituted heteroaryl, or        haloalkyl; or R₉, R₁₀, and the carbon atom to which they are        attached form an optionally substituted cycloalkyl;    -   R₁₁ of ULM-j is optionally substituted heterocyclic, optionally        substituted alkoxy, optionally substituted heteroaryl,        optionally substituted aryl, or

-   -   R₁₂ of ULM-j is H or optionally substituted alkyl;    -   R₁₃ of ULM-j is H, optionally substituted alkyl, optionally        substituted alkylcarbonyl, optionally substituted        (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl; optionally substituted (oxoalkyl)carbamate,    -   each R₁₄ of ULM-j is independently H, haloalkyl, optionally        substituted cycloalkyl, optionally substituted alkyl or        optionally substituted heterocycloalkyl;    -   R₁₅ of ULM-j is H, optionally substituted heteroaryl, haloalkyl,        optionally substituted aryl, optionally substituted alkoxy, or        optionally substituted heterocyclyl;    -   each R₁₆ of ULM-j is independently halo, optionally substituted        alkyl, optionally substituted haloalkyl, CN, or optionally        substituted haloalkoxy;    -   each R₂₅ of ULM-j is independently H or optionally substituted        alkyl; or both R₂₅ groups can be taken together to form an oxo        or optionally substituted cycloalkyl group;    -   R₂₃ of ULM-j is H or OH;    -   Z₁, Z₂, Z₃, and Z₄ of ULM-j are independently C or N; and    -   of ULM-j is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable        salt, stereoisomer, solvate or polymorph thereof.

In certain embodiments, wherein G of ULM-j is C=J, J is O, R₇ is H, eachR₁₄ is H, and o is 0.

In certain embodiments, wherein G of ULM-j is C=J, J is O, R₇ is H, eachR₁₄ is H, R₁₅ is optionally substituted heteroaryl, and o is 0. In otherinstances, E is C═O and M is

In certain embodiments, wherein E of ULM-j is C═O, R₁₁ is optionallysubstituted heterocyclic or

and M is

In certain embodiments, wherein E of UTM-j is C═O, M is

and R₁₁ is

each R₁₈ is independently halo, optionally substituted alkoxy, cyano,optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1,2, 3, or 4.

In certain embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   G of ULM-k is C=J, J is O;    -   R₇ of ULM-k is H;    -   each R₁₄ of ULM-k is H;    -   o of ULM-k is O;    -   R₁₅ of ULM-k is

and

-   -   R₁₇ of ULM-k is H, halo, optionally substituted cycloalkyl,        optionally substituted alkyl, optionally substituted alkenyl,        and haloalkyl.

In other instances, R₁₇ of ULM-k is alkyl (e.g., methyl) or cycloalkyl(e.g., cyclopropyl).

In other embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   G of ULM-k is C=J, J is O;    -   R₇ of ULM-k is H;    -   each R₁₄ of ULM-k is H;    -   o of ULM-k is 0; and    -   R₁₅ of ULM-k is selected from the group consisting of:

-   -   wherein R₃₀ of ULM-k is H or an optionally substituted alkyl.

In other embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   E of ULM-k is C═O;    -   M of ULM-k is

and

-   -   R₁₁ of ULM-k is selected from the group consisting of:

In still other embodiments, a compound of the chemical structure,

wherein:

-   -   E of ULM-k is C═O;    -   R¹¹ of ULM-k is

-   -   M of ULM-k is

-   -   q of ULM-k is 1 or 2;    -   R₂₀ of ULM-k is H, optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, or

-   -   R₂₁ of ULM-k is H or optionally substituted alkyl; and    -   R₂₂ of ULM-k is H, optionally substituted alkyl, optionally        substituted alkoxy, or haloalkyl.

In any embodiment described herein, R₁₁ of ULM-j or ULM-k is selectedfrom the group consisting of:

In certain embodiments, R₁₁ of ULM-j or ULM-k is selected from the groupconsisting of:

In certain embodiments, ULM (or when present ULM′) is a group accordingto the chemical structure:

wherein:

-   -   X of ULM-1 is O or S;    -   Y of ULM-1 is H, methyl or ethyl;    -   R₁₇ of ULM-1 is H, methyl, ethyl, hydroxymethyl or cyclopropyl;    -   M of ULM-1 is optionally substituted aryl, optionally        substituted heteroaryl, or

-   -   R_(9 of ULM-1) is H;    -   R₁₀ of ULM-1 is H, optionally substituted alkyl, optionally        substituted haloalkyl, optionally substituted heteroaryl,        optionally substituted aryl, optionally substituted        hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;    -   R11 of ULM-1 is optionally substituted heteroaromatic,        optionally substituted heterocyclic, optionally substituted aryl        or

-   -   R₁₂ of ULM-1 is H or optionally substituted alkyl; and    -   R₁₃ of ULM-1 is H, optionally substituted alkyl, optionally        substituted alkylcarbonyl, optionally substituted        (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl; optionally substituted (oxoalkyl)carbamate.

In some embodiments, ULM and where present, ULM′, are each independentlya group according to the chemical structure:

wherein:

-   -   Y of ULM-m is H, methyol or ethyl    -   R₉ of ULM-m is H;    -   R₁₀ is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or        cyclohexyl;    -   R₁₁ of ULM-m is optionally substituted amide, optionally        substituted isoindolinone, optionally substituted isooxazole,        optionally substituted heterocycles.

In other proffered embodiments of the invention, ULM and where present,ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   R₁₇ of ULM-n is methyl, ethyl, or cyclopropyl; and    -   R₉, R₁₀, and R₁₁ of ULM-n are as defined above. In other        instances, R₉ is H; and    -   R₁₀ of ULM-n is H, alkyl, or cycloalkyl (preferably, isopropyl,        tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

In any of the aspects or embodiments described herein, the ULM (or whenpresent, ULM′) as described herein may be a pharmaceutically acceptablesalt, enantiomer, diastereomer, solvate or polymorph thereof. Inaddition, in any of the aspects or embodiments described herein, the ULM(or when present, ULM′) as described herein may be coupled to a PTMdirectly via a bond or by a chemical linker.

In certain aspects of the invention, the ULM moiety is selected from thegroup consisting of:

wherein the VLM may be connected to a PTM via a linker, as describedherein, at any appropriate location, including, e.g., an aryl,heteroary, phenyl, or phenyl of an indole group, optionally via anyappropriate functional group, such as an amine, ester, ether, alkyl, oralkoxy.

Exemplary CLMs:

In any aspect or embodiment described herein, the description providescompounds useful for binding and/or inhibiting cereblon (e.g., the ULMis a CLM, the PTM is a CLM, or both the ULM and PTM are CLMs).

In some embodiments, the ULM is a CLM that is a thalidomide,lenalidomide, pomalidomide, analogs thereof, isosteres thereof, orderivatives thereof.

Neo-Imide Compounds

In certain embodiments, the CLM is selected from the group consisting ofchemical structures:

wherein:

-   -   W is selected from the group consisting of CH₂, CHR, C═O, SO₂,        NH, and N-alkyl;    -   each X is independently selected from the group consisting of O,        S, and H₂;    -   Y is selected from the group consisting of CH₂, —C═CR′, NH,        N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and        S;    -   Z is selected from the group consisting of O, S, and H₂;    -   G and G′ are independently selected from the group consisting of        H, alkyl (linear, branched, optionally substituted with R′), OH,        R′OCOOR, R′OCONRR″, CH₂-heterocyclyl optionally substituted with        R′, and benzyl optionally substituted with R′;    -   Q₁, Q₂, Q₃, and Q₄ represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   A is independently selected from the group H, alkyl, cycloalkyl,        Cl and F;    -   R comprises but is not limited to:—CONR′R″, —OR′, —NR′R″, —SR′,        —SO₂R′, —SO₂NR′R″, —CR′R″—, —CR′NR′R″—, -aryl, -hetaryl, -alkyl        (linear, branched, optionally substituted), -cycloalkyl,        -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″,        —OP(O)R′R″, —Cl, —F, —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″,        —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″,        —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′,        —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ or        —OCF₃;    -   R′ and R″ are independently selected from the group consisting        of a bond, H, N, N-oxide, alkyl (linear, branched), cycloalkyl,        aryl, heteroaryl, heterocyclic, —C(═O)R, or heterocyclyl, each        of which is optionally substituted;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   R_(n) comprises a functional group or an atom,    -   wherein n is an integer from 1-4, and wherein:        -   when n is 1, R_(n) is modified to be covalently joined to            the linker group (L), and        -   when n is 2, 3, or 4, then one R_(n) is modified to be            covalently joined to the linker group (L), and any other            R_(n) is optionally modified to be covalently joined to a            PTM, a CLM, a second CLM having the same chemical structure            as the CLM, a CLM′, a second linker, or any multiple or            combination thereof.

Exemplary CLMs

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W is independently selected from the group CH₂, CHR, C═O, SO₂,        NH, and N-alkyl;    -   X is independently selected from the group O, S and H₂;    -   Y is independently selected from the group CH₂, —C═CR′, NH,        N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and        S;    -   Z is independently selected from the group O, and S or H₂ except        that both X and Z cannot be H2;    -   G and G′ are independently selected from the group H, alkyl        (linear, branched, optionally substituted with R′), OH, R′OCOOR,        R′OCONRR″, CH₂-heterocyclyl optionally substituted with R′, and        benzyl optionally substituted with R′;    -   Q1-Q4 represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   A is independently selected from the group H, alkyl, cycloalkyl,        Cl and F;    -   R comprises, but is not limited to: —CONR′R″, —OR′, —NR′R″,        —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—, —CR′NR′R″—, -aryl, -hetaryl,        -alkyl (linear, branched, optionally substituted), -cycloalkyl,        -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″,        —OP(O)R′R″, —Cl, —F, —Br, —I, —CF3, —CN, —NR′SO₂NR′R″,        —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″,        —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′,        —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ or        —OCF₃    -   R′ and R″ are independently selected from the group consisting        of a bond, H, N, N-oxide, alkyl (linear, branched), cycloalkyl,        aryl, heteroaryl, heterocyclic, —C(═O)R, or heterocyclyl, each        of which is optionally substituted;    -   n is an integer from 1-4;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   Rn comprises 1-4 independent functional groups or atoms, and        optionally, one of which is modified to be covalently joined to        a ABM, a chemical linker group (L), a ULM, CLM (or CLM′) or        combination thereof.

In certain embodiments described herein, the CLM or ULM comprises achemical structure selected from the group:

wherein:

-   -   W is independently selected from the group CH₂, C═O, NH, and        N-alkyl;    -   R is independently selected from a H, methyl, alkyl;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   Rn comprises 1-4 independently selected functional groups or        atoms, and optionally, one of which is modified to be covalently        joined to a PTM, a chemical linker group (L), a CLM (or CLM′) or        combination thereof.

In some embodiments, the CLM is represented by the following structureswith the dashed lines indicating linker attachment points:

More specifically, non-limiting examples of CLMs include those shownbelow as well as those “hybrid” molecules that arise from thecombination of 1 or more of the different features shown in themolecules below.

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W of Formulas (h) through (ab) is independently selected from        CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   Q₁, Q₂, Q₃, Q₄, Q₅ of Formulas (h) through (ab) are        independently represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   R¹ of Formulas (h) through (ab) is selected from H, CN, C₁-C₃        alkyl;    -   R² of Formulas (h) through (ab) is selected from the group H,        CN, C₁-C₃ alkyl, CHF₂, CF₃, CHO;    -   R³ of Formulas (h) through (ab) is selected from H, alkyl,        substituted alkyl, alkoxy, substituted alkoxy;    -   R⁴ of Formulas (h) through (ab) is selected from H, alkyl,        substituted alkyl;    -   R⁵ of Formulas (h) through (ab) is H or lower alkyl;    -   X of Formulas (h) through (ab) is C, CH or N;    -   R′ of Formulas (h) through (ab) is selected from H, halogen,        alkyl, substituted alkyl, alkoxy, substituted alkoxy;    -   R of Formulas (h) through (ab) is H, OH, lower alkyl, lower        alkoxy, cyano, halogenated lower alkoxy, or halogenated lower        alkyl    -   of Formulas (h) through (ab) is a single or double bond; and    -   the CLM is covalently joined to a PTM, a chemical linker group        (L), a ULM, CLM (or CLM′) or combination thereof.

In any aspect or embodiment described herein, the CLM or CLM′ iscovalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, aCLM′, or a combination thereof via an R group (such as, R, R¹, R², R³,R⁴ or R′), W, X, or a Q group (such as, Q₁, Q₂, Q₃, Q₄, or Q₅) ofFormulas (h) through (ab).

In any of the embodiments described herein, the CLM or CLM′ iscovalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, aCLM′, or a combination thereof via W, X, R, R¹, R², R³, R⁴, R⁵, R′, Q₁,Q₂, Q₃, Q₄, and Q₅ of Formulas (h) through (ab).

In any of the embodiments described herein, the W, X, R¹, R², R³, R⁴,R′, Q₁, Q₂, Q₃, Q₄, and Q₅ of Formulas (h) through (ab) canindependently be covalently coupled to a linker and/or a linker to whichis attached to one or more PTM, ULM, ULM′, CLM or CLM′ groups.

More specifically, non-limiting examples of CLMs include those shownbelow as well as “hybrid” molecules or compounds that arise fromcombining 1 or more features of the following compounds:

wherein:

-   -   W of Formulas (ac) through (an) is independently selected from        the group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   R¹ of Formulas (ac) through (an) is selected from the group H,        CN, C₁-C₃ alkyl;    -   R³ of Formulas (ac) through (an) is selected from H, alkyl,        substituted alkyl, alkoxy, substituted alkoxy;    -   R of Formulas (ac) through (an) is H;    -   is a single or double bond; and    -   Rn of Formulas (ac) through (an) comprises a functional group or        an atom.

In any of the embodiments described herein, the W, R¹, R², Q₁, Q₂, Q₃,Q₄, and Rn of Formulas (ac) through (an) can independently be covalentlycoupled to a linker and/or a linker to which is attached one or morePTM, ULM, ULM′, CLM or CLM′ groups.

In any of the embodiments described herein, the R¹, R², Q₁, Q₂, Q₃, Q₄,and Rn of Formulas (ac) through (an) can independently be covalentlycoupled to a linker and/or a linker to which is attached one or morePTM, ULM, ULM′, CLM or CLM′ groups.

In any of the embodiments described herein, the Q₁, Q₂, Q₃, Q₄, and Rnof Formulas (ac) through (an) can independently be covalently coupled toa linker and/or a linker to which is attached one or more PTM, ULM,ULM′, CLM or CLM′ groups.

In any aspect or embodiment described herein, R_(n) of Formulas (ac)through (an) is modified to be covalently joined to the linker group(L), a PTM, a ULM, a second CLM having the same chemical structure asthe CLM, a CLM′, a second linker, or any multiple or combinationthereof.

In any aspect or embodiment described herein, the CLM is selected from:

wherein R′ is a halogen and R¹ is as described above with regard toFormulas (h) through (ab) or (ac) through (an).

In certain cases, the CLM can be imides that bind to cereblon E3 ligase.These imides and linker attachment point can be but not limited to thefollowing structures:

wherein R′ is a halogen.

Exemplary Linkers:

In any of the aspects or embodiments comprising the structure ULM-L-PTM,the linker (L) comprises a chemical structural unit represented by theformula:

-(A)_(q)-,

wherein:

A is a group which is connected to a ULM or PTM moiety; and

q is an integer greater than or equal to 1,

wherein A is selected from the group consisting of a bond,CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3), SO₂NR^(L3), SONR^(L3), CONR^(L3),NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO, CR^(L1)═CR^(L2), C≡C,SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1), NR^(L3)C(═NCN)NR^(L4),NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4), C₃₋₁₁cycloalkyl optionallysubstituted with 0-6 R^(L1) and/or R^(L2) groups, C₃₋₁₁heterocyclyloptionally substituted with 0-6 R^(L1) and/or R^(L2) groups, aryloptionally substituted with 0-6 R^(L1) and/or R^(L2) groups, heteroaryloptionally substituted with 0-6 R^(L1) and/or R^(L2) groups, whereR^(L1) or R^(L2), each independently are optionally linked to othergroups to form cycloalkyl and/or heterocyclyl moiety, optionallysubstituted with 0-4 R^(L5) groups;

-   -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl,        NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈cycloalkyl, SC₁₋₈cycloalkyl,        NHC₁₋₈cycloalkyl, N(C₁₋₈cycloalkyl)₂,        N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH, SO₂C₁₋₈alkyl,        P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈alkyl,        CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),        C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃,        Si(OH)(C₁₋₈alkyl)₂, COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂,        CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl,        SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂,        N(C₁₋₈alkyl)CONH(C₁₋₈alkyl), N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂,        NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂, NHCONH₂,        N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NH        SO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.

In any aspect or embodiment described herein, the linker (L) comprisesthe following chemical structure:

wherein:

-   -   W^(L1) and W^(L2) are each independently a 4-8 membered ring        with 0-4 heteroatoms, optionally substituted with RQ, each RQ is        independently a H, halo, OH, CN, CF3, C1-C6 alkyl (linear,        branched, optionally substituted), C1-C6 alkoxy (linear,        branched, optionally substituted), or 2 RQ groups taken together        with the atom they are attached to, form a 4-8 membered ring        system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C1-C6 alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; or C1-C6 alkoxy (linear, branched,        optionally substituted); and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In any aspect or embodiment described herein, the linker (L) comprisesthe following chemical structure:

wherein:

-   -   W^(L1) and W^(L2) are each independently aryl, heteroaryl,        cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl,        biheteroaryl, or biheterocyclic, each optionally substituted        with RQ, each RQ is independently a H, halo, OH, CN, CF₃,        hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), OC₁₋₃alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 RQ groups taken together with the atom        they are attached to, form a 4-8 membered ring system containing        0-4 heteroatoms;    -   Y^(L1) is each independently a bond, NR^(YL1), O, S, NR^(YL2),        CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   Q^(L) is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally bridged, optionally substituted with 0-6        R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), or 2 R^(Q) groups taken together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   R^(YL1), R^(YL2) are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In some of the embodiments, linker (L) comprises a group represented bya general structure selected from the group consisting of:

-   -   —N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,        —O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,        —O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;        —N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;        —(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;        —(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—;

wherein each m, n, o, p, q, and r, is independently 0, 1, 2, 3, 4, 5, 6with the proviso that when the number is zero, there is no N—O or O—Obond; R is selected from the group H, methyl or ethyl, and X is selectedfrom the group H or F;

In some additional embodiments, linker (L) is selected from the groupconsisting of:

In some preferred embodiments, linker (L) is selected from the groupconsisting of:

wherein each n and m is independently 0, 1, 2, 3, 4, 5, or 6.

In some embodiments, L is an optionally substituted polyethylenoxy groupcomprising from 1 to 10 units.

In some additional embodiments, L is a polyethylene group optionallysubstituted with aryl or phenyl comprising from 1 to 10 ethylene glycolunits.

In any of the embodiments, the compound comprises multiple ULMs,multiple PTMs, multiple linkers or any combinations thereof.

Exemplary Tau-PROTAC Compounds

As described above, in certain aspects, the description providesbifunctional PROTAC compounds comprising at least one PTM group, alinker, and at least one ULM (VLM or CLM) group as described herein.

In certain embodiments, the compound is selected from the groupconsisting of compounds 1-330 (e.g., selected from Table 1 or 2), andsalts and polymorphs thereof.

In certain embodiments, the compound is selected from Table 1 or 2(i.e., the compound is selected from Compounds 1-330), and salts andpolymorphs thereof.

In any aspect or embodiment described herein, the compound is selectedfrom Formulas CI through CV:

wherein:

-   -   R¹⁰¹ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl or cyano;    -   R¹⁰² is selected from H, alkyl, haloalkyl, cycloalkyl or        heterocycloalkyl;    -   R¹⁰³ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl or cyano;    -   R¹⁰⁴ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl or cyano;    -   R¹⁰⁵ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl or cyano;    -   R¹⁰⁶, R¹⁰⁷, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, R¹¹⁴, R¹¹⁶, R¹¹⁷,        R¹²⁰, R¹²¹, R¹²⁶, R¹²⁷, R¹²² and R¹²³ are each independently        selected from H, alkyl, halogen or haloalkyl;    -   R¹⁰⁸ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl, cyano or methoxy;    -   R¹¹⁵ is selected from H, alkyl and haloalkyl;    -   R¹¹⁸ and R¹¹⁹ are independently selected from H, alkyl, halogen        or haloalkyl, or R¹¹⁸ and R¹¹⁹ taken together with the carbon        atom to which they are attached represent a 3-6-membered        cycloalkyl or heterocycloalkyl ring, such as cyclopropane or an        oxetane;    -   R¹²⁴ and R¹²⁵ are independently selected from H, alkyl, halogen        or haloalkyl, or R¹²⁴ and R¹²⁵ taken together with the carbon        atom to which they are attached represent a 3-6-membered        cycloalkyl or heterocycloalkyl ring, such as cyclopropane or an        oxetane;    -   G is a phenyl or a 5- or 6-membered heteroaryl ring; and    -   Z is CH₂ or C═O.

In any aspect or embodiment described herein, at least one of:

-   -   R¹⁰¹ is H, F or Cl;    -   R¹⁰² is H, CH₃, or CF₂H;    -   R¹⁰³ is H or F;    -   R¹⁰⁴ is H, CH₃, F or CN;    -   R¹⁰⁵ is H, CN, CH₃ or CF₃;    -   R¹⁰⁶ and R¹⁰⁷ are each independently H, F or CH₃;    -   R¹⁰⁸ is H, F or CH₃O;    -   R¹⁰⁹ and R¹¹⁰ are each independently H or CH₃;    -   R¹¹¹ and R¹¹² are each independently H, F or CH₃;    -   R¹¹³ and R¹¹⁴ are each independently H or CH₃;    -   R¹¹⁵ is H or CH₃;    -   R¹¹⁶ and R¹¹⁷ are each independently H or CH₃;    -   R¹¹⁸ and R¹¹⁹ are each independently H, CH₃, F, or R¹¹⁸ and R¹¹⁹        taken together with the carbon atom to which they are attached        represent a cyclopropane or an oxetane ring;    -   R¹²⁰ and R¹²¹ are each independently H or CH₃;    -   R¹²² and R¹²³ are each independently H or CH₃;    -   R¹²⁴ and R¹²⁵ are each independently H, CH₃, F, or R¹²⁴ and R¹²⁵        taken together with the carbon atom to which they are attached        represent a cyclopropane or an oxetane ring;    -   R¹²⁶ and R¹²⁷ are each independently H or CH₃;    -   A is a pyridine or a pyrimidine;    -   Z is CH₂ or C═O; or    -   a combination thereof.

In any aspect or embodiment described herein, the compound is selectedfrom the group consisting of:(2S,4R)-1-((S)-14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-2-tert-butyl-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(1);4-(2-(2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(2);4-(2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(3);4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(4);(2S,4R)-1-((S)-2-(2-(2-(2-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(5);(2S,4R)-1-((S)-17-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-2-tert-butyl-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(6);(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(7);(2S,4R)-1-((S)-2-tert-butyl-15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa-3-azapentadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(8);(2S,4R)-1-((S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaoctadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(9);(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(10);(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide(11);(2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide(12);(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide(13);(2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide(14);(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(15);(2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(16);(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(17);(2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(18);(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(19);(2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(20);(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(21);(2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(22);(2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(23);(2S,4R)-1-((S)-17-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,17-dioxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(24);4-((2-(2-(2-(2-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(25);4-((14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(26);(2S,4R)-1-((S)-2-(2-(2-(2-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(27);(2S,4R)-1-((S)-2-(2-(2-(2-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(28);(2S,4R)-1-((S)-2-tert-butyl-14-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(29);(2S,4R)-1-((S)-2-tert-butyl-14-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12-trioxa-3-azatetradecane)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(30);(2S,4R)-1-((S)-2-tert-butyl-17-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(31);(2S,4R)-1-((S)-2-tert-butyl-17-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecane)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(32);(2S,4R)-1-((S)-2-(2-(4-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)butoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(33);(2S,4R)-1-((S)-2-(2-(4-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)butoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(34);(2S,4R)-1-((S)-2-(2-(3-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(35);(2S,4R)-1-((S)-2-(2-(3-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(36);(2S,4R)-1-((S)-2-(2-(5-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)pentyloxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(37);(2S,4R)-1-((S)-2-(2-(5-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)pentyloxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(38);(2S,4R)-1-((S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-4-oxo-6,9,12,15-tetraoxa-3-azaoctadecane)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(39);4-(15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-3,6,9,12-tetraoxapentadecylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(40);4-((2-(2-(2-(2-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(41);4-((14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(42);(2S,4R)-1-((2S)-2-tert-butyl-15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-14-hydroxy-4-oxo-6,9,12-trioxa-3-azapentadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(43);4-(2-(2-(2-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)propoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(44);4-(15-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-14-hydroxy-3,6,9,12-tetraoxapentadecylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(45);(2S,4R)-1-((2S)-2-tert-butyl-18-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-17-hydroxy-4-oxo-6,9,12,15-tetraoxa-3-azaoctadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(46);4-(2-(2-(2-(3-(2-(4-(dimethylamino)phenyl)quinolin-6-yloxy)-2-hydroxypropoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(47);2-(2,6-dioxopiperidin-3-yl)-4-(14-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecylamino)isoindoline-1,3-dione(48);3-(4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecylamino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(49);3-(4-(14-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)-3,6,9,12-tetraoxatetradecyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(50);5-((14-((5-(5H-Pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(51);5-((5-(4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(52); 5-(4-(3-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(53);5-((5-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(54);5-(3-(6-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pyridin-3-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(55); 5-((5-(4-(2-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(56);5-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)piperidin-1-yl)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(57);5-((5-(2-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)ethoxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(58); 5-((5-(4-(2-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(59); 5-(4-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(60);2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione(61);3-(5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(62);2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione(63); 5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(64); 5-((5-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(65); 5-(4-(2-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(66);2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione(67); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)piperazin-1-yl)isoindoline-1,3-dione(68);2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione(69); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione(70);2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-yl)oxy)isoindoline-1,3-dione(71);5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-4,6,7-trifluoroisoindoline-1,3-dione(72); [5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione](73);2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione(74);2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)piperidin-1-yl)isoindoline-1,3-dione(75);2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione(76); 5-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(77); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)piperazin-1-yl)isoindoline-1,3-dione(78);2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)azetidin-1-yl)isoindoline-1,3-dione(79);2-(2,6-dioxopiperidin-3-yl)-5-((1-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)azetidin-3-yl)oxy)isoindoline-1,3-dione(80);5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione(81); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)isoindoline-1,3-dione(82); 5-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(83); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenoxy)hexyl)oxy)isoindoline-1,3-dione(84); 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)cyclobutoxy)isoindoline-1,3-dione(85);4-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(86);6-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (87);2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione(88);2-(2,6-dioxopiperidin-3-yl)-5-(4-(3,3,3-trifluoro-2-(2-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)ethoxy)propyl)piperidin-1-yl)isoindoline-1,3-dione(89);2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)but-2-yn-1-yl)oxy)butoxy)butoxy)isoindoline-1,3-dione(90); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(8-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)octyl)piperazin-1-yl)isoindoline-1,3-dione(91);5-((14-((3-chloro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(92);5-((6-((5-(2,2-difluoro-2-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)ethoxy)pentyl)oxy)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(93); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione(94); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pentyl)oxy)isoindoline-1,3-dione(95); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)-3-(trifluoromethyl)piperazin-1-yl)isoindoline-1,3-dione(96); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione(97); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hexyl)oxy)isoindoline-1,3-dione(98); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione(99);2-(2,6-dioxopiperidin-3-yl)-5-(6-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)butoxy)butoxy)-2-azaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione(100); 5-((1-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(101); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione(102);5-((14-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(103); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(104); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione(105);2-(2,6-dioxopiperidin-3-yl)-5-((5-((5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidin-1-yl)pentyl)oxy)pentyl)oxy)isoindoline-1,3-dione(106);2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)butoxy)butoxy)isoindoline-1,3-dione(107); 2-(2,6-dioxopiperidin-3-yl)-5-((6-((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione(108); 2-(2,6-dioxopiperidin-3-yl)-5-((6-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione(109); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hexyl)oxy)isoindoline-1,3-dione(110); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione(111);5-((14-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(112);5-((14-((4-chloro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(113); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)pentyl)oxy)isoindoline-1,3-dione(114);2-(2,6-dioxopiperidin-3-yl)-5-((5-((5-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)azetidin-3-yl)oxy)pentyl)oxy)pentyl)oxy)isoindoline-1,3-dione(115);2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)butoxy)butyl)-2-azaspiro[3.3]heptan-6-yl)oxy)isoindoline-1,3-dione(116); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione(117); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione(118);(2S,4R)-1-((S)-17-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(119);(2S,4R)-1-((S)-2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(120);(2S,4R)-1-((S)-20-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(121);(2S,4R)-1-((S)-23-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18,21-hexaoxa-3-azatricosanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(122); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)isoindoline-1,3-dione(123); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione(124); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(125); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)pentyl)oxy)isoindoline-1,3-dione(126);3-(5-(4-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(127);3-(5-(4-(2-(1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(128);2-(2,6-dioxopiperidin-3-yl)-5-((1,1,1-trifluoro-6-(2-(2-(2-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)hexan-2-yl)oxy)isoindoline-1,3-dione(129);2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(130);2-(2,6-dioxopiperidin-3-yl)-5-((17-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)isoindoline-1,3-dione(131);2-(2,6-dioxopiperidin-3-yl)-5-((20-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15,18-hexaoxaicosyl)oxy)isoindoline-1,3-dione(132);2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)hexyl)azetidin-1-yl)isoindoline-1,3-dione(133); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione(134); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione(135); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione(136); 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)isoindoline-1,3-dione(137);5-((14-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(138);2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-fluoro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione(139);2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione(140); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione(141); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione(142);2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-6-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione(143); 2-(2,6-dioxopiperidin-3-yl)-5-(6-(6-((1s,3s)-3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy)pyridin-3-yl)hex-5-ynyloxy)isoindoline-1,3-dione (144);2-(2,6-dioxopiperidin-3-yl)-5-(6-(6-((1s,3s)-3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy) pyridin-3-yl)hexyloxy)isoindoline-1,3-dione(145);2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione(146); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)hexyl)oxy)isoindoline-1,3-dione(147); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(148); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hexyl)oxy)isoindoline-1,3-dione](149); 5-(6-(2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(150); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hexyl)oxy)isoindoline-1,3-dione(151); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione(152); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3,3,3-trifluoro-2-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)propyl)azetidin-1-yl)isoindoline-1,3-dione(153); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2,2,2-trifluoro-1-((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)oxy)ethyl)azetidin-1-yl)isoindoline-1,3-dione(154); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)pyridin-2-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione(155); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione(156); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione(157); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridazin-4-yl)oxy)ethoxy)isoindoline-1,3-dione(158); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione(159); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione(160); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione(161); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)butoxy)azetidin-1-yl)isoindoline-1,3-dione(162); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione(163); 5-(6-(4-((1r,3r)-3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy)piperidin-1-yl)-6-oxohexyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(164); 5-((5-((1-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(165); 5-((5-((1-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(166);2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione(167);2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione(168); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)oxetan-3-yl)methoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(169); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(170); 5-((4,4-difluoro-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(171); 5-((6-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)hex-5-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(172); 5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(173); 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)butoxy)isoindoline-1,3-dione(174);2-(2,6-dioxopiperidin-3-yl)-5-((5-((3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pentyl)oxy)isoindoline-1,3-dione(175); 5-(3-(3-(3-((1r,3r)-3-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(176); 3-(5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(177); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)oxy)methyl)azetidin-1-yl)isoindoline-1,3-dione(178); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione(179); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(180); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)ethyl)azetidin-1-yl)isoindoline-1,3-dione(181); 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(182); 5-((3-(5-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(183);2-(2,6-dioxopiperidin-3-yl)-5-((7-(3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)heptyl)oxy)isoindoline-1,3-dione(184);(2S,4R)—N-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(185);(2S,4R)—N-(2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(186);(2S,4R)—N-(2-(2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(187); 5-(2-((3-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(188); 5-((3-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenyl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(189); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethyl)azetidin-1-yl)isoindoline-1,3-dione(190); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)propoxy)methyl)azetidin-1-yl)isoindoline-1,3-dione(191); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)methyl)azetidin-1-yl)isoindoline-1,3-dione(192);2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-oxoethoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(193); 5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(194);5-((14-((5-(4-chloro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(195);(2S,4R)—N-(2-(2-(2-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(196); 5-(6-((2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(197); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione(198);3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butoxy)methyl)-N-methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)bicyclo[1.1.1]pentane-1-carboxamide(199); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((7-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)heptyl)oxy)azetidin-1-yl)isoindoline-1,3-dione(200);(2S,4R)—N-(2-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(201);2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methoxy)-N-methyl-N-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)acetamide(202);2-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile(203); 5-((3-(5-((1r,3r)-3-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(204); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)propoxy)isoindoline-1,3-dione(205); 2-(2,6-dioxopiperidin-3-yl)-5-(3-((2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)methyl)azetidin-1-yl)isoindoline-1,3-dione(206);5-((14-((5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(207);2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)azetidin-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione(208); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)ethoxy)ethoxy)isoindoline-1,3-dione(209);2-(2,6-dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperazin-1-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione(210);2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)ethoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(211); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)but-2-yn-1-yl)oxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione(212); 2-(2,6-dioxopiperidin-3-yl)-5-(6-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)-2-azaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione(213); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)piperazin-1-yl)isoindoline-1,3-dione(214);2-(2,6-dioxopiperidin-3-yl)-5-((1R,3r)-3-(isopropyl(2-(3-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethyl)amino)cyclobutoxy)isoindoline-1,3-dione(215); 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethoxy)piperidin-1-yl)isoindoline-1,3-dione(216);2-(2,6-dioxopiperidin-3-yl)-5-((1R,3r)-3-((2-(3-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)ethyl)amino)cyclobutoxy)isoindoline-1,3-dione(217);2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(4-fluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione(218); 3-(5-((3-(5-((1r,3r)-3-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(219); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(220); 3-(5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(221); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(222); 3-(5-((3-(6-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(223); 3-(5-(3-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(224); 3-(5-(3-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(225); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-4,6-difluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(226);3-(5-((1R,3r)-3-((3-(5-((1r,3R)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)cyclobutoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(227); 3-(5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(228); 2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-N-methylacetamide(229);3-(5-((1R,3r)-3-((3-(5-((1r,3R)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)cyclobutyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(230); 3-(5-((3-(6-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(231); 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrazin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(232); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(233); 3-(5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(234); 2-((1r,3r)-3-((6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile(235); 5-(2-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(236); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione(237); 2-((1r,3r)-3-((6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile(238); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(239); 3-(5-(2-((3-(5-((1r,3r)-3-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(240); 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(241); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione(242); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(243); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione(244); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(245); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione(246); 3-(5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(247); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)isoindoline-1,3-dione(248); 3-(5-(2-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(249); 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)hex-2-yn-1-yl)oxy)isoindoline-1,3-dione(250); 3-(5-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)hex-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(251);2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidin-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione(252);N-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)ethyl)-N-methyl-4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butanamide(253); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-2-oxoethyl)azetidin-3-yl)oxy)isoindoline-1,3-dione(254); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-2-oxoethoxy)azetidin-1-yl)isoindoline-1,3-dione(255); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenoxy)azetidin-1-yl)isoindoline-1,3-dione(256); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(257); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(9-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy)isoindoline-1,3-dione(258); 2-(2,6-dioxopiperidin-3-yl)-5-((4-(9-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)but-2-yn-1-yl)oxy)isoindoline-1,3-dione(259); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)piperazin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione(260); 2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)piperazin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione(261); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(3-(((1s,3s)-1-hydroxy-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methoxy)propoxy)propoxy)ethoxy)isoindoline-1,3-dione(262);2-(2,6-dioxopiperidin-3-yl)-5-(2-(3-(3-((3-hydroxy-1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)azetidin-3-yl)methoxy)propoxy)propoxy)ethoxy)isoindoline-1,3-dione(263);2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((5′-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3′H-spiro[cyclobutane-1,2′-furo[2,3-b]pyridin]-3-yl)oxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione(264);5-((14-((5-(6,8-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(265);2-(2,6-dioxopiperidin-3-yl)-5-((14-((1-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperidin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione(266);2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((1R,3r)-3-(2-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)cyclobutyl)ethoxy)azetidin-1-yl)isoindoline-1,3-dione(267);2-(2,6-dioxopiperidin-3-yl)-5-(3-((1S,2R)-2-((4-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)methyl)cyclopropyl)azetidin-1-yl)isoindoline-1,3-dione(268);2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(((1R,2R)-2-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)cyclopropyl)methoxy)butoxy)azetidin-1-yl)isoindoline-1,3-dione(269);2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(((1R,2R)-2-((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)cyclopropyl)methoxy)ethoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione(270);2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((1R,3r)-3-(((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)cyclobutoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione(271); 5-(3-(3-(2,2-difluoro-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(272); 5-(3-(2,2-difluoro-3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(273); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)propoxy)isoindoline-1,3-dione(274); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)isoindoline-1,3-dione(275); 5-(2-((1,1-difluoro-3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(276); 3-(5-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(277); 3-(5-(((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(278); 3-(5-(3-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)oxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(279); 5-(3-((4-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)oxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(280); 5-(3-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(281); 3-(5-(3-((5-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(282); 2-(2,6-dioxopiperidin-3-yl)-5-((1-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione(283); 3-(5-((1-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-1-yl)azetidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(284); 5-(2-(2,2-difluoro-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)propoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(285); 2-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)-5-(5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile(286); 3-(5-((3-(5-((1r,3r)-3-((3-methyl-5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(287); 3-(5-((3-(5-((1r,3r)-3-((5-(4-chloro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(288); 3-(5-((3-(5-((1r,3r)-3-((5-(4-fluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(289); 3-(5-((3-(5-((1r,3r)-3-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(290); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione(291);2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-((1R,3r)-3-(((1r,3R)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)cyclobutyl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione(292); 3-(5-(4-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(293); 6-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (294); 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione(295);2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isonicotinonitrile(296);2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isonicotinonitrile(297); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(4-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione(298); 3-(5-(2-((3-(4-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(299); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-4-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-4-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione(301);6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)picolinonitrile(302);6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)prop-1-yn-1-yl)-3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)picolinonitrile(303); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(6-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione(304); 3-(5-(2-((3-(6-methyl-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(305); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-6-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)isoindoline-1,3-dione(306); 3-(5-(2-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)-6-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(307); 2-(2,6-dioxopiperidin-3-yl)-5-(2-((2-methyl-4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)isoindoline-1,3-dione(308); 3-(5-(2-((2-methyl-4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)but-3-yn-2-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(309); 3-(5-(2-(1-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)ethynyl)cyclopropoxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(310); 2-(2,6-dioxopiperidin-3-yl)-5-(2-(1-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)ethynyl)cyclopropoxy)ethoxy)isoindoline-1,3-dione(311);4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile(312);4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile(313); 3-(5-((3-(4-methyl-3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(314); 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(315); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-5-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(316);6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)nicotinonitrile(317);3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile(318);3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)benzonitrile(319); 3-(5-((3-(3-methyl-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(320); 3-(5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(321); 3-(5-((3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-6-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(322); 3-(5-((3-(2-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(323); 2-(2,6-dioxopiperidin-3-yl)-5-((2-methyl-4-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)but-3-yn-2-yl)oxy)isoindoline-1,3-dione(324); 3-(5-((2-methyl-4-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)but-3-yn-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(325); 3-(5-((2-methyl-4-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)but-3-yn-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(326); 3-(5-((1,1-difluoro-3-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(327); 3-(5-((2-methyl-4-(4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyrimidin-2-yl)but-3-yn-2-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(328);6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-3-methylbut-1-yn-1-yl)-4-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)nicotinonitrile(329);2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)-3-methylbut-1-yn-1-yl)-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)isonicotinonitrile(330).

The present description includes, where applicable, the compositionscomprising the pharmaceutically acceptable salts, in particular, acid orbase addition salts of compounds of the present disclosure.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastic juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts, among numerousother acids and bases well known in the pharmaceutical art. Sodium andpotassium salts are particularly preferred as neutralization salts ofthe phosphates according to the present disclosure.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the aforementioned base compounds useful in thisdisclosure are those which form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3 naphthoate)]salts, among numerousothers.

Pharmaceutically acceptable base addition salts may also be used toproduce pharmaceutically acceptable salt forms of the compounds orderivatives according to the present disclosure. The chemical bases thatmay be used as reagents to prepare pharmaceutically acceptable basesalts of the present compounds that are acidic in nature are those thatform non-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (eg.,potassium and sodium) and alkaline earth metal cations (eg, calcium,zinc and magnesium), ammonium or water-soluble amine addition salts suchas N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines, amongothers.

Compositions:

In another aspect, the description provides compositions comprisingcompounds as described herein, including salts thereof, and apharmaceutically acceptable carrier. In certain embodiments, thecompositions are therapeutic or pharmaceutical compositions comprisingan effective amount of a compound as described herein and apharmaceutically acceptable carrier.

The amount of compound in a pharmaceutical composition of the instantdisclosure that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host and diseasetreated, the particular mode of administration. Generally, an amountbetween 0.1 mg/kg and 1000 mg/kg body weight/day of active ingredientsis administered dependent upon potency of the agent. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED50 (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD50/ED50.Compounds that exhibit large therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage touninfected cells and, thereby, reduce side effects. The data obtainedfrom the cell culture assays and animal studies can be used informulating a range of dosage for use in humans. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED50 with little or no toxicity. The dosage may varywithin this range depending upon the dosage form employed and the routeof administration utilized. For any compound used in the method of thepresent disclosure, the therapeutically effective dose can be estimatedinitially from cell culture assays. A dose may be formulated in animalmodels to achieve a circulating plasma concentration range that includesthe IC50 (i.e., the concentration of the test compound which achieves ahalf-maximal inhibition of symptoms) as determined in cell culture. Suchinformation can be used to more accurately determine useful doses inhumans. Levels in plasma may be measured, for example, by highperformance liquid chromatography.

The compositions of the present disclosure may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers and may also be administered in controlled-releaseformulations. Pharmaceutically acceptable carriers that may be used inthese pharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

In any of the aspects or embodiments described herein, the PTM, ULM orboth have an affinity (IC₅₀) for their respective target protein of lessthan about 500 μM, 450 μM, 400 μM, 350 μM, 300 μM, 250 μM, 200 μM, 150μM, 100 μM, 50 μM, 10 μM, 0.10 μM, 0.01 μM, 0.001 μM, 0.1 nM, 0.01 nM,0.001 nM or less. The determination of the IC₅₀ can be performed usingmethods well known to those of skill in the art in view of the presentdisclosure.

In any of the aspects or embodiments, the compounds as described hereineffectuate the ubquitination of a target protein at sufficient levels oramounts to effectuate or induce degradation of the target protein.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount for the desired indication, withoutcausing serious toxic effects in the patient treated. A preferred doseof the active compound for all of the herein-mentioned conditions is inthe range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kgper day, more generally 0.5 to about 25 mg per kilogram body weight ofthe recipient/patient per day. A typical topical dosage will range from0.01-5% wt/wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing less than 1 mg, 1 mgto 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosageform. An oral dosage of about 25-250 mg is often convenient.

The active ingredient is preferably administered to achieve peak plasmaconcentrations of the active compound of about 0.00001-30 mM, preferablyabout 0.1-30 μM. This may be achieved, for example, by the intravenousinjection of a solution or formulation of the active ingredient,optionally in saline, or an aqueous medium or administered as a bolus ofthe active ingredient. Oral administration is also appropriate togenerate effective plasma concentrations of active agent.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

Liposomal suspensions may also be pharmaceutically acceptable carriers.These may be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811 (which isincorporated herein by reference in its entirety). For example, liposomeformulations may be prepared by dissolving appropriate lipid(s) (such asstearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline,arachadoyl phosphatidyl choline, and cholesterol) in an inorganicsolvent that is then evaporated, leaving behind a thin film of driedlipid on the surface of the container. An aqueous solution of the activecompound is then introduced into the container. The container is thenswirled by hand to free lipid material from the sides of the containerand to disperse lipid aggregates, thereby forming the liposomalsuspension.

Modes of Administration

In any of the aspects or embodiments described herein, the therapeuticcompositions comprising compounds described herein can be in anysuitable dosage form configured to be delivered by any suitable route.For example, the compounds can be administered by any appropriate route,for example, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, including transdermally, in liquid, cream,gel, or solid form, rectally, nasally, buccally, vaginally or via animplanted reservoir or by aerosol form.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally, intraperitoneally or intravenously.

The compounds as described herein may be administered in single ordivided doses by the oral, parenteral or topical routes. Administrationof the active compound may range from continuous (intravenous drip) toseveral oral administrations per day (for example, Q.I.D.) and mayinclude oral, topical, parenteral, intramuscular, intravenous,sub-cutaneous, transdermal (which may include a penetration enhancementagent), buccal, sublingual and suppository administration, among otherroutes of administration. Enteric coated oral tablets may also be usedto enhance bioavailability of the compounds from an oral route ofadministration. The most effective dosage form will depend upon thepharmacokinetics of the particular agent chosen as well as the severityof disease in the patient.

Administration of compounds as sprays, mists, or aerosols forintra-nasal, intra-tracheal or pulmonary administration may also beused. Compounds as described herein may be administered in immediaterelease, intermediate release or sustained or controlled release forms.Sustained or controlled release forms are preferably administeredorally, but also in suppository and transdermal or other topical forms.Intramuscular injections in liposomal form may also be used to controlor sustain the release of compound at an injection site.

Sterile injectable forms of the compositions as described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions as described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added. Oral compositions willgenerally include an inert diluent or an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the active compound or its prodrugderivative can be incorporated with excipients and used in the form oftablets, troches, or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials are included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a dispersing agent such as alginicacid, Primogel, or corn starch; a lubricant such as magnesium stearateor Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or entericagents.

The active compound or pharmaceutically acceptable salt thereof can beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

Alternatively, the pharmaceutical compositions as described herein maybe administered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient, which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the disclosure may also beadministered topically. Suitable topical formulations are readilyprepared for each of these areas or organs. Topical application for thelower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-acceptable transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this disclosure include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In certain preferred aspects of the disclosure, the compounds may becoated onto a stent which is to be surgically implanted into a patientin order to inhibit or reduce the likelihood of occlusion occurring inthe stent in the patient.

Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this disclosure may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

A patient or subject in need of therapy using compounds as describedherein can be treated by administering to the patient (subject) aneffective amount of the compound including pharmaceutically acceptablesalts, solvates or polymorphs, thereof optionally in a pharmaceuticallyacceptable carrier or diluent, either alone, or in combination withother known agents.

Co-Administration

Disease states of conditions which may be treated using compounds orcompositions according to the present description include, but notlimited to, for example, cancer (e.g., prostate cancer), and Kennedy'sdisease. In certain embodiments, the therapeutic or pharmaceuticalcompositions comprise an effective amount of an additional biologicallyor bioactive active agent, e.g., an agent effective for the treatment ofcancer, that is co-administered.

The term “co-administration” or “combination therapy” shall mean that atleast two compounds or compositions are administered to the patient atthe same time, such that effective amounts or concentrations of each ofthe two or more compounds may be found in the patient at a given pointin time. Although compounds according to the present disclosure may beco-administered to a patient at the same time, the term embraces bothadministration of two or more agents at the same time or at differenttimes, provided that effective concentrations of all co-administeredcompounds or compositions are found in the subject at a given time. Incertain preferred aspects of the present disclosure, one or more of thepresent compounds described above, are co-administered in combinationwith at least one additional bioactive agent, especially including ananticancer agent. In particularly preferred aspects of the disclosure,the co-administration of compounds results in synergistic therapeutic,including anticancer therapy.

In another aspect, the description provides a composition comprising aneffective amount of two or more of the PROTAC compounds as describedherein, and a pharmaceutically acceptable carrier. In certainembodiments, the composition further comprises an effective orsynergistic amount of another bioactive agent that is not a PROTACcompound.

Pharmaceutical compositions comprising combinations of an effectiveamount of at least one bifunctional compound according to the presentdisclosure, and one or more of the compounds otherwise described herein,all in effective amounts, in combination with a pharmaceuticallyeffective amount of a carrier, additive or excipient, represents afurther aspect of the present disclosure.

The term “bioactive agent” is used to describe an agent, other than thePROTAC compounds described herein, which is used in combination with thepresent compounds as an agent with biological activity to assist ineffecting an intended therapy, inhibition and/or prevention/prophylaxisfor which the present compounds are used. Preferred bioactive agents foruse herein include those agents which assist in effecting an intendedtherapy, for example, P-gp inhibitors or agents that havepharmacological activity similar to that for which the present compoundsare used or administered and include for example, anti-neurodegenerativeagents.

The term “P-gp” is used to describe “permeability glycoprotein” orP-glycoprotein (ABCB1) which was discovered in 1976 in rodent cells. Thepresence of “endogenous or physiological” P-gp is a potential problem toachieving targeted exposure with therapeutic agents. P-gp is expressedat barrier tissue to sanctuary sites (e.g., blood-brain barrier) and atsecretory/absorptive tissues (e.g., gastrointestinal tract)(Cordon-Cardo et al., 1989, 1990). The protein acts as a cellulardefender and influences the overall pharmacokinetic profile of numerousdrugs by actively pumping them out of the intracellular environment(effluxing) thereby reducing drug penetration of the barrier tissues. Inparticular, P-gp efflux reduces drug permeability across thegastrointestinal tract membranes and may lead to reduced systemicexposure of the drug. P-gp efflux also reduces drug access across theblood-brain barrier. P-gp inhibitors could indirectly contribute toefficacy by increasing PROTAC exposure, particularly CNS exposure

The term “additional anti-neurodegenerative agent” is used to describean anti-neurodegenerative agent, which may be combined with PROTACcompounds according to the present description to treat neurodenerativediseases.

In certain embodiments, the PROTAC(s) are used along with P-gpinhibitors.

In certain additional embodiments, the P-gp inhibitors are selected fromthe group consisting of, but not limited to, Amiodarone, Azithromycin,Captopril, Clarithromycin, Cyclosporine, Piperine, Quercetin, Quinidine,Quinine, Reserpine, Ritonavir, Tariquidar, Elacridar and Verapamil.

Methods of Treatment

In another aspect, the disclosure provides methods of modulating proteinubiquitination and degradation in a subject, e.g., a cell, a tissue,mammal, or human patient, the method comprising administering aneffective amount of a PROTAC compound as described herein or acomposition comprising an effective amount of the same to a subject,wherein the compound or composition comprising the same is effective inmodulating protein ubquitination and degradation of the protein in thesubject. In certain embodiments, the protein is Tau protein.

In certain embodiments, the description provides a method for regulatingprotein activity of Tau protein by degenerating Tau aggregates in apatient in need comprising administering to said patient an amount of acompound as described herein to a patient.

In still additional embodiments, the description provides a method oftreating a disease state or condition in a patient wherein dysregulatedprotein activity (Tau aggregation and accumulation) is responsible forsaid disease state or condition, said method comprising administering tosaid patient an effective amount of a compound as described herein tosaid patient in order to regulate said protein activity in said patient.In certain embodiments, the protein is Tau.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Disease states or conditions,including neurological and neurodegenerative diseases, which may betreated using compounds according to the present disclosure are setforth hereinabove.

In another aspect, the disclosure provides methods of modulating Tauprotein ubiquitination and degradation in a subject, e.g., a cell, atissue, mammal, or human patient, the method comprising administering aneffective amount of a compound as described herein or a compositioncomprising an effective amount of a compound as described herein to asubject, wherein the compound or composition comprising the same iseffective in modulating Tau protein ubquitination and degradation of theprotein in the subject.

In another aspect, the disclosure provides methods of treating orameliorating a symptom of a disease related to Tau accumulation oraggregation in a subject, e.g., a cell, a tissue, mammal, or humanpatient, the method comprising administering an effective amount of acompound as described herein or a composition comprising an effectiveamount of the same to a subject in need thereof, wherein the compound orcomposition comprising the same is effective in treating or amelioratinga symptom of a disease related to Tau aggregation in the subject.

In certain embodiments, the disease or disorder is a neurologicaldisorder including but not limited to Absence of the Septum Pellucidum,Acquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis,ADHD, Adie's Pupil, Adie's Syndrome, Adreno-leukodystrophy, Agenesis ofthe Corpus Callosum, Agnosia, Aicardi Syndrome, AIDS-NeurologicalComplications, Alexander Disease, Alpers' Disease, AlternatingHemiplegia, Alzheimer's Disease, Amyotrophic Lateral Sclerosis,Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Aphasia,Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari Malformation,Arteriovenous Malformation, Asperger Syndrome, Ataxia, Ataxia,Telangiectasia, Ataxias and Cerebellar/Spinocerebellar Degeneration,Attention Deficit-Hyperactivity Disorder, Autism, Autonomic Dysfunction,Back Pain, Barth Syndrome Batten Disease, Becker's Myotonia, Behcet'sDisease, Bell's Palsy, Benign Essential Blepharospasm, Benign FocalAmyotrophy, Benign Intracranial Hypertension, Bernhardt-Roth Syndrome,Binswanger's Disease, Blepharospasm, Bloch-Sulzberger Syndrome, BrachialPlexus Birth Injuries, Brachial Plexus Injuries, Bradbury-EgglestonSyndrome, Brain and Spinal Tumors, Brain Aneurysm, Brain Injury,Brown-Sequard Syndrome, Bulbospinal Muscular Atrophy, Canavan Disease,Carpal Tunnel Syndrome Causalgia, Cavernomas, Cavernous Angioma,Cavernous Malformation, Central Cervical Cord Syndrome, Central CordSyndrome, Central Pain Syndrome, Cephalic Disorders, CerebellarDegeneration, Cerebellar Hypoplasia, Cerebral Aneurysm, CerebralArteriosclerosis, Cerebral Atrophy, Cerebral Beriberi, CerebralGigantism, Cerebral Hypoxia, Cerebral Patsy,Cerebro-Oculo-Facio-Skeletal Syndrome, Charcot-Marie-Tooth Disease,Chiari Malformation, Chorea, Choreoacanthocytosis, Chronic InflammatoryDemyelinating Polyneuropathy (CIDP), Chronic Orthostatic Intolerance,Chronic Pain Cockayne Syndrome Type II, Coffin Lowry Syndrome, COFS,Colpocephaly, Coma and Persistent Vegetative State, Complex RegionalPain Syndrome, Congenital Facial Diplegia, Congenital Myasthenia,Congenital Myopathy, Congenital Vascular Cavernous, Malformations,Corticobasal Degeneration, Cranial Arteritis, Craniosynostosis,Creutzfeldt-Jakob Disease, Cumulative Trauma Disorders, Cushing'sSyndrome, Cytomegalic Inclusion Body Disease, Cytomegalovirus Infection,Dancing Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome, DawsonDisease, De Morsier's Syndrome, Deep Brain Stimulation for Parkinson'sDisease, Dejerine-Klumpke Palsy, Dementia, Dementia-Multi-Infarct,Dementia-Semantic, Dementia-Subcortical, Dementia With Lewy Bodies,Dentate Cerebellar Ataxia, Dentatorubral Atrophy, Dermatomyositis,Developmental Dyspraxia, Devic's Syndrome, Diabetic Neuropathy, DiffuseSclerosis, Dysautonomia, Dysgraphia, Dyslexia, Dysphagia, Dyspraxia,Dyssynergia Cerebellaris, Myoclonica, Dyssynergia CerebellarisProgressiva, Dystonias, Early Infantile Epileptic, Encephalopathy, EmptySella Syndrome, Encephalitis Lethargica, Encephaloceles, Encephalopathy,Encephalotrigeminal Angiomatosis, Epilepsy, Erb-Duchenne andDejerine-Klumpke Palsies, Erb's Palsy, Fabry's Disease, Fahr's Syndrome,Fainting, Familial Dysautonomia, Familial Hemangioma, FamilialIdiopathic Basal Ganglia, Calcification, Familial Periodic Paralyses,Familial Spastic Paralysis, Febrile Seizures, Fisher Syndrome, FloppyInfant Syndrome, Friedreich's Ataxia, Frontotemporal, Dementia,Gaucher's Disease, Gerstmann's Syndrome, Gerstmann-Straussler-Scheinker,Disease, Giant Cell Arteritis, Giant Cell Inclusion Disease, GloboidCell Leukodystrophy, Glossopharyngeal Neuralgia, Guillain-BarreSyndrome, Hallervorden-Spatz Disease, Head Injury, Headache, HemicraniaContinua, Hemifacial Spasm, Hemiplegia Alterans, HereditaryNeuropathies, Hereditary Spastic Paraplegia, Heredopathia AtacticaPolyneuritiformis, Herpes Zoster, Herpes Zoster Oticus, HirayamaSyndrome, Holmes-Adie syndrome, Holoprosencephaly, HTLV-1 Associated,Myelopathy, Huntington's Disease, Hydranencephaly, Hydrocephalus,Hydrocephalus-Normal Pressure, Hydromyelia, Hyperactivity,Hypercortisolism, Hypersomnia, Hypertonia, Hypotonia,—Infantile,Hypoxia, Immune-Mediated Encephalomyelitis, Inclusion Body Myositis,Incontinentia Pigmenti, Infantile Hypotonia, Infantile NeuroaxonalDystrophy, Infantile Phytanic Acid Storage Disease, Infantile RefsumDisease, Infantile Spasms, Inflammatory Myopathy, Iniencephaly,Intestinal Lipodystrophy, Intracranial Cysts, Intracranial Hypertension,Isaac's Syndrome, Joubert Syndrome, Kearns-Sayre Syndrome, Kennedy'sDisease, Kinsbourne syndrome, Kleine-Levin Syndrome, Klippel-FeilSyndrome, Klippel-Trenaunay Syndrome (KTS), Klüver-Bucy Syndrome,Korsakoffs Amnesic Syndrome, Krabbe Disease, Kugelberg-Welander Disease,Kuru, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome,Lateral Femoral, Cutaneous Nerve Entrapment, Lateral Medullary Syndrome,Learning Disabilities, Leigh's Disease, Lennox-Gastaut Syndrome,Lesch-Nyhan Syndrome, Leukodystrophy, Levine-Critchley Syndrome, LewyBody Dementia, Lipid Storage Diseases, Lissencephaly, Locked-InSyndrome, Lou Gehrig's Disease, Lupus-Neurological, Sequelae, LymeDisease-Neurological Complications, Machado-Joseph Disease,Macrencephaly, Mania, Megalencephaly, Melkersson-Rosenthal Syndrome,Meningitis, Meningitis and Encephalitis, Menkes Disease, MeralgiaParesthetica, Metachromatic, Leukodystrophy, Microcephaly, Migraine,Miller Fisher Syndrome, Mini-Strokes, Mitochondrial Myopathies, MobiusSyndrome, Monomelic Amyotrophy, Motor Neuron Diseases, Moyamoya Disease,Mucolipidoses, Mucopolysaccharidoses, Multifocal Motor Neuropathy,Multi-Infarct Dementia, Multiple Sclerosis, Multiple System Atrophy,Multiple System Atrophy with Orthostatic Hypotension, MuscularDystrophy, Myasthenia-Congenital, Myasthenia Gravis, MyelinoclasticDiffuse Sclerosis, Myoclonic Encephalopathy of Infants, Myoclonus,Myopathy, Myopathy-Congenital, Myopathy-Thyrotoxic, Myotonia, MyotoniaCongenita, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with BrainIron Accumulation, Neurofibromatosis, Neuroleptic Malignant Syndrome,Neurological Complications of AIDS, Neurological Complications Of LymeDisease, Neurological Consequences of Cytomegalovirus Infection,Neurological Manifestations of Pompe Disease, Neurological Sequelae OfLupus, Neuromyelitis Optica, Neuromyotonia, Neuronal Ceroid,Lipofuscinosis, Neuronal Migration Disorders, Neuropathy—Hereditary,Neurosarcoidosis, Neurotoxicity, Nevus Cavernosus, Niemann-Pick Disease,Normal Pressure Hydrocephalus, Occipital Neuralgia, Obesity, OccultSpinal Dysraphism Sequence, Ohtahara Syndrome, OlivopontocerebellarAtrophy, Opsoclonus Myoclonus, Orthostatic Hypotension,O'Sullivan-McLeod Syndrome, Overuse Syndrome, Pain—Chronic, Paine,Pantothenate Kinase-Associated Neurodegeneration, ParaneoplasticSyndromes, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis,Paroxysmal Hemicrania, Parry-Romberg, Pelizaeus-Merzbacher Disease, PenaShokeir II Syndrome, Perineural Cysts, Periodic Paralyses, PeripheralNeuropathy, Periventricular Leukomalacia, Persistent Vegetative State,Pervasive Developmental Disorders, Phytanic Acid Storage Disease, Pick'sDisease, Pinched Nerve, Piriformis Syndrome, Pituitary Tumors,Polymyositis, Pompe Disease, Porencephaly, Postherpetic Neuralgia,Postinfectious Encephalomyelitis, Post-Polio Syndrome, PosturalHypotension, Postural Orthostatic, Tachycardia Syndrome, PosturalTachycardia Syndrome, Primary Dentatum Atrophy, Primary LateralSclerosis, Primary Progressive Aphasia, Prion Diseases, ProgressiveHemifacial Atrophy, Progressive Locomotor Ataxia, ProgressiveMultifocal, Leukoencephalopathy, Progressive Sclerosing Poliodystrophy,Progressive Supranuclear, Palsy, Prosopagnosia, Pseudotumor Cerebri,Ramsay Hunt Syndrome I (formerly known as), Ramsay Hunt Syndrome II(formerly known as), Rasmussen's Encephalitis, Reflex SympatheticDystrophy Syndrome, Refsum Disease, Refsum Disease—Infantile, RepetitiveMotion Disorders, Repetitive Stress Injuries, Restless Legs Syndrome,Retrovirus-Associated Myelopathy, Rett Syndrome, Reye's Syndrome,Riley-Day Syndrome, Sacral Nerve Root Cysts, Saint Vitus Dance, SalivaryGland Disease, Sandhoff Disease, Schilder's Disease, Schizencephaly,Seitelberger Disease, Seizure Disorder, Semantic Dementia, Septo-OpticDysplasia, Shaken Baby Syndrome, Shingles Shy-Drager Syndrome, Sjogren'sSyndrome, Sleep Apnea, Sleeping Sickness, Sotos Syndrome, Spasticity,Spina Bifida, Spinal Cord Infarction, Spinal Cord Injury, Spinal CordTumors, Spinal Muscular Atrophy, Spinocerebellar Atrophy,Spinocerebellar, Degeneration, Steele-Richardson-Olszewski Syndrome,Stiff-Person Syndrome, Striatonigral Degeneration, Stroke, Sturge-WeberSyndrome, Subacute Sclerosing Panencephalitis, SubcorticalArteriosclerotic Encephalopathy, SUNCT Headache Swallowing Disorders,Sydenham Chorea, Syncope, Syphilitic Spinal Sclerosis,Syringohydromyelia, Syringomyelia, Systemic Lupus Erythematosus, TabesDorsalis Tardive Dyskinesia, Tarlov Cysts, Tay-Sachs Disease, TemporalArteritis, Tethered Spinal Cord Syndrome, Thomsen's Myotonia, ThoracicOutlet Syndrome, Thyrotoxic Myopathy, Tic Douloureux, Todd's Paralysis,Tourette Syndrome, Transient Ischemic Attack, Transmissible SpongiformEncephalopathies, Transverse Myelitis, Traumatic Brain Injury, Tremor,Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis,Vascular Erectile Tumor, Vasculitis including Temporal Arteritis, VonEconomo's Disease, Von Hippel-Lindau Disease (VHL), Von Recklinghausen'sDisease, Wallenberg's Syndrome, Werdnig-Hoffman Disease,Wernicke-Korsakoff Syndrome, West Syndrome, Whiplash, Whipple's Disease,Williams Syndrome, Wilson's Disease, X-Linked Spinal and Bulbar MuscularAtrophy, or Zellweger Syndrome.

In certain embodiments, the disease or disorder is at least one ofHuntington's disease, muscular dystrophy, Parkinson's disease,Alzheimer's disease, Batten disease, Injuries to the spinal cord andbrain, Seizure disorders, epilepsy, brain tumors, meningitis, autoimmunediseases such as multiple sclerosis, Neurofibromatosis, Depression,Amyotrophic Lateral Sclerosis, Arteriovenous Malformation, BrainAneurysm, Dural Arteriovenous Fistulae, Headache, Memory Disorders,Peripheral Neuropathy, Post-Herpetic Neuralgia, Spinal Cord Tumor andStroke.

In certain embodiments, the disease or disorder is Alzheimer's disease.

In another aspect, the disclosure provides methods of treating orameliorating a symptom of a disease related to Tau accumulation oraggregation in a subject, e.g., a cell, a tissue, mammal, or humanpatient, the method comprising administering an effective amount of acompound as described herein or a composition comprising an effectiveamount of the same and an effective or synergistic amount of anotherbioactive agent to a subject in need thereof, wherein the compositioncomprising the same is effective in treating or ameliorating a symptomof a disease related to Tau accumulation or aggregation in the subjectby Tau degradation/inhibition.

In certain embodiments, the disease to be treated is Neurologicaldisorder. In a preferred embodiment, the subject is a human.

In certain additional embodiments, the additional bioactive agent is ananti-neurodegenerative agent.

In alternative aspects, the present disclosure relates to a method fortreating a disease state by degrading a protein or polypeptide throughwhich a disease state or condition is modulated comprising administeringto said patient or subject an effective amount of at least one compoundas described hereinabove, optionally in combination with an additionalbioactive agent. The method according to the present disclosure may beused to treat a large number of neurological disease states orconditions, by virtue of the administration of effective amounts of atleast one compound described herein.

In another aspect, the disclosure provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

Kits

In another aspect, the description provides kits comprising compounds orcompositions as described herein. The kit may be promoted, distributed,or sold as a unit for performing the methods of the present disclosure.In addition, the kits of the present disclosure may preferably containinstructions, which describe a suitable use. Such kits can beconveniently used, e.g., in clinical settings, to treat patients withNeurological disorders.

Examples

The PROTAC compounds of the instant disclosure are effective in Taudegradation. Exemplary compounds are presented in Tables 1 and 2 with invitro data of some selected compounds in Tables 2 and 3 showingdegradation of tau protein. In vivo studies showing degradation of tauprotein are illustrated in the FIGURE.

General Methods of Chemical Synthesis

The synthesis of the claimed chimeric compounds can be carried outaccording to the general synthetic procedures known in literature.Synthetic routes shown in the schemes in the present disclosure aredescribed as one of the methods that can be used to obtain the desiredcompounds. Other methods can also be used for those skilled in the artof synthesis. The ULM and PTM described in schemes only represent one ofmany ULMs and PTMs in this application.

LC-MS Method for Purity Analysis (Quality Control)

LCMS Method:

Instrumentations: Agilent infinity 1260 LC; Agilent 6230 TOF massspectrometer

The analysis is conducted on a Poroshell 120 EC C18 column (50 mm×3.0 mminternal diameter 2.7 μm packing diameter) at 45° C.

The solvents employed are:

A=0.1% v/v solution of formic acid in water.

B=0.1% v/v solution of formic acid in acetonitrile.

The gradient employed are as follows:

Time Flow Rate (minutes) (mL/min) % A % B 0 1 95 5 0.5 1 95 5 3.0 1 1 994.0 1 1 99 4.1 1 95 5 4.5 1 95 5

The UV detection is an averaged signal from wavelength of 210 nm to 350nm and mass spectra are recorded on a mass spectrometer using positivemode electrospray ionization.

Abbreviations

ACN: acetonitrile

Boc₂O: di-tert-butyl dicarbonate

DCM: dichloromethane.

DIPEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DMF: N,N-dimethylformamide

EA: ethyl acetate

HATU: 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

HPLC: high-performance liquid chromatography

LC-MS: liquid chromatography-mass spectrometry

Min: minutes

MTBE: methyl tert-butyl ether

PE: petroleum ether

RT: room temperature

SPB: sodium perborate

tBu: tert-butyl

TBACl: tetra-butyl ammonium chloride

TFA: trifluoroacetic acid

THF: tetrahydrofuran

TLC: thin layer chromatography

TMS: trimethylsilyl

t_(R): retention rime

TsCl: p-toluene sulfonyl chloride

Intermediates of Ubiquitin E3 Ligase Targeting Moiety (ULM) and ProteinTargeting Moiety (PTM)

Intermediate 1: (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamidehydrochloride (ULM-1)

Step 1: Preparation of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile

To a stirred solution of 4-bromobenzonitrile (20 g, 109.88 mmol) in DMA(250 mL) under a nitrogen atmosphere was added 4-methyl-1,3-thiazole(21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) andpotassium acetate (21.66 g, 220.71 mmol) at room temperature. Theresulting mixture was heated to 150° C. and stirred at this temperaturefor 5 hours, at which time LC-MS indicated completion of the reaction.The mixture was cooled to room temperature, diluted with 1 L of waterand extracted with ethyl acetate (300 mL×3). The organic layers werecombined, washed with brine (200 mL), dried over anhydrous sodiumsulfate and then concentrated under reduced pressure to give a cruderesidue, which was purified by flash silica gel column chromatography(eluent: ethyl acetate/petroleum ether, v:v=1:5) to give the titledcompound (yield: 91%) as a white solid.

Step 2: Preparation of [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine

To a stirred solution of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (35g, 174.77 mmol) in tetrahydrofuran (1000 mL) was added LiAlH₄ (20 g,526.32 mmol) in portions at 0° C. in 10 minutes under a nitrogenatmosphere. The resulting mixture was then stirred at 60° C. for 3hours, at which time LC-MS indicated completion of reaction. The mixturewas cooled to 0° C., then quenched by the addition of water (20 mL,added slowly), aq. solution of NaOH (15%, 20 mL) and water (60 mL). Theresulting mixture was then extracted with ethyl acetate (300 mL×2). Theorganic layers were combined, washed with brine (100 mL), dried overanhydrous sodium sulfate and then concentrated under reduced pressure togive a crude residue, which was purified by flash silica gel columnchromatography (eluent: dichloromethane/methanol (v:v=10:1)) to give thetitled compound (yield: 56%) as a yellow oil.

Step 3: Preparation of tert-butyl(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate

To a stirred solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid(2.7 g, 11.68 mmol) in N,N-dimethylformamide (20 mL) was added DIPEA(2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine (2 g, 9.79 mmol) atroom temperature. The resulting mixture was stirred at room temperatureovernight, at which time LC-MS indicated completion of reaction. Thereaction mixture was diluted with 20 mL of water and extracted withethyl acetate (50 mL×3). The organic layers were combined, washed withbrine (50 mL), dried over anhydrous sodium sulfate and then concentratedunder reduced pressure to give a crude residue, which was purified byflash silica gel column chromatography (eluent: dichloromethane/methanol(v:v=20:1)) to give the titled compound (yield: 56%) as a yellow solid.

Step 4: Preparation of(2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamidehydrochloride

To 1 L round bottom flask containing tert-butyl(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate(45 g, 107.78 mmol) in dioxane was added hydrogen chloride in dioxane(4N, 300 mL). The resulting solution was stirred for 2 hours at roomtemperature. The solids were collected by filtration to give the titledproduct (yield: 98%) as a yellow solid.

Step 5: Preparation of tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

To a stirred solution of(2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoic acid (15.7 g,68.0 mmol) in N,N-dimethylformamide (500 mL) was added DIPEA (29.2 g,225.9 mmol), HATU (25.9 g, 68.1 mmol) and(2S,4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)-phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (20.0 g, 56.5 mmol) at roomtemperature.

The resulting solution was stirred at room temperature for 16 hours,LC-MS indicated formation of the desired product. The reaction mixturewas diluted by water (200 mL) and extracted with ethyl acetate (200mL×3). The organic layers were combined, washed with saturated aqueoussolution of sodium chloride (50 mL×2), dried over anhydrous sodiumsulfate and then concentrated under reduced pressure to give a cruderesidue, which was purified by flash silica gel chromatography (eluent:ethyl acetate/petroleum ether (v:v=2:1)) to give the title compound(yield: 51%) as a yellow solid.

Step 6: Synthesis of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamidehydrochloride (ULM-1)

To a stirred solution of tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate(12 g, 22.61 mmol) in dioxane (20 mL) was added a solution of hydrogenchloride in dioxane (4N, 80 mL) at room temperature. The resultingsolution was stirred at room temperature for 2 hours, at which timeLC-MS indicated completion of reaction. Precipitated solids werecollected by filtration to give the titled product (yield: 48%) as ayellow solid.

d: 48%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ 9.84-9.82 (s, 1H), 7.58-7.54 (m, 4H),4.71-4.41 (m, 4H), 4.13-4.08 (m, 1H), 3.86-3.71 (m, 2H), 3.36 (s, 1H),2.60-2.58 (s, 3H), 2.35-2.07 (m, 2H), 1.19-1.12 (m, 9H). LC-MS (ES⁺):m/z 431.11 [MH⁺], t_(R)=0.73 min.

Intermediate 2:(2S,4R)-1-[(S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N—[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl]-pyrrolidine-2-carboxamidehydrochloride (ULM-2)

Step 1: Preparation of (S)-tert-butyl-1-(4-bromophenyl)-ethyl carbamate

To a mixture of (S)-1-(4-bromophenyl)ethanamine (3.98 g, 19.9 mmol) andNaHCO₃ (1.24 g, 14.8 mmol) in H₂O (10 mL) and ethyl acetate (10 mL) wasadded (Boc)₂O (5.20 g, 23.8 mmol) at 5° C. The reaction was continued toreact for 2 hours. TLC showed reaction was complete. The reactionmixture was filtered. The solid was collected and suspended in a mixtureof hexane (10 mL) and H₂O (10 mL) for 0.5 hours. The mixture wasfiltered and the solid was collected and dried in oven at 50° C. toafford the title compound as white solid (5.9 g, 98.7%).

¹HNMR (400 MHz, DMSO-d₆): δ 1.28 (d, J=7.2 Hz, 3H), 1.36 (s, 9H),4.55-4.60 (m, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.39 (br, 1H), 7.49 (d, J=8.4Hz, 2H).

Step 2: Preparation of (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanaminehydrochloride

A mixture of (S)-tert-butyl-1-(4-bromophenyl)-ethyl carbamate (4.0 g,13.3 mmol), 4-methylthiazole (2.64 g, 26.6 mmol), palladium (II) acetate(29.6 mg, 0.13 mmol) and potassium acetate (2.61 g, 26.6 mmol) in DMF(10 mL) was stirred at 90° C. under N2 for 18 hours. After cooling toambient temperature, the reaction mixture was filtered. To the filtratewas added H₂O (50 mL) and the resulting mixture was stirred at ambienttemperature for 4 hours. The reaction mixture was filtered. The solidwas collected by filtration and dried in oven at 50° C. to afford(S)-tert-butyl 1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (3.48 g,82.3%) as gray solid.

¹HNMR (400 MHz, DMSO-d₆): δ 1.33 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 2.46(s, 3H), 4.64-4.68 (m, 1H), 7.23 (br d, 0.5H), 7.39 (d, J=8 Hz, 2H),7.44 (d, J=8.4 Hz, 2H), 7.50 (br d, 0.5H), 8.99 (s, 1H); LC-MS [M+1]⁺:319.5

This solid material (1.9 g, 6.0 mmol) was dissolved in 4N hydrochloridein methanol (5 mL, 20 mmol, prepared from acetyl chloride and methanol)and the mixture was stirred at ambient temperature for 3 h thenconcentrated and triturated with ether. The mixture was filtered and thesolid was collected and dried in oven at 60° C. to afford(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (1.3 g,85%) as a light green solid.

¹HNMR (400 MHz, DMSO-d6): δ 1.56 (d, J=6.8 Hz, 3H), 2.48 (s, 3H),4.41-4.47 (m, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz), 8.75 (s,3H), 9.17 (s, 1H); LC-MS [M+1]⁺: 219.2

Step 3: Preparation of (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylicacid

HATU (2.15 g, 5.7 mmol) was added to a solution of(S)-2-(tert-butoxycarbonyl)amino-3,3-dimethylbutanoic acid (1.25 g, 5.4mol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride(0.98 g, 5.4 mmol) and DIPEA (2.43 g, 18.9 mmol) in DMF (10 mL) at 0° C.under nitrogen. The mixture was stirred at ambient temperature for 18hours. TLC showed the reaction complete. The reaction mixture wasquenched with water (30 mL) and extracted with ethyl acetate (15 mL×4).The combined organic layer was washed with the 5% citric acid (10 mL×2),saturated NaHCO₃ solution (10 mL×2), brine (10 mL×2) and dried overNa₂SO₄. The organic solution was filtered and concentrated to afford(2S, 4R)-methyl1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylateas pale yellow oil (1.93 g, 100% yield). This crude product (1.93 g) andlithium hydroxide hydrate (2.2 g, 54 mmol) were taken into THF (20 mL)and H₂O (10 mL). The resulting mixture was stirred at ambienttemperature for 18 hours. THF was removed by concentration. The residuewas diluted with ice-water (10 mL) and slowly adjusted to pH 2-3 with 3NHCl. The resulting suspension was filtered, washed with H₂O (6 mL×2).The solid was collected by filtration and dried in oven at 50° C. toafford the title compound as a white solid (1.4 g, 75% for two steps).¹HNMR (400 MHz, DMSO-d₆): δ 6.50 (d, J=9.6 Hz, 1H), 5.19 (br s, 1H),4.32 (br s, 1H), 4.25 (t, J=8.4 Hz, 1H), 4.16 (d, J=9.2 Hz, 1H),3.57-3.66 (m, 2H), 2.08-2.13 (m, 1H), 1.85-1.91 (m, 1H), 1.38 (s, 9H),0.94 (s, 9H).

Step 4: Preparation of(2S,4R)-1-[(S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N—[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl]-pyrrolidine-2-carboxamidehydrochloride (ULM-2)

HATU (1.6 g, 4.2 mmol) was added to a stirred solution containing (2S,4R)-1-{(S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}-4-hydroxypyrrolidine-2-carboxylicacid (1.21 g, 3.5 mmol),(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine hydrochloride (0.9 g,3.5 mmol), and DIPEA (1.36 g, 10.5 mmol) in anhydrous THF (15 mL) at 0°C. The resulting mixture was allowed to warm up to ambient temperatureand continued to stir for 2 hours. TLC showed reaction completed. THFwas removed by concentration. To the residue was added water (15 mL) andthe resulting mixture was stirred for 4 hours. The resulting mixture wasfiltered. The solid was collected and dried in oven at 50° C. to give awhite solid. This solid was taken into methanol (10 mL) and activatedcarbon (150 mg) was added. The resulting mixture was heated at 80° C.and stirred for 1 h. The mixture was filtered while it was hot. Water (5mL) was added to the filtrate at 80° C. The resulting mixture was cooledto ambient temperature and continued to stir for 18 hours. Thesuspension was filtered. The solid was collected and dried in oven at50° C. to affordtert-butyl-{(S)-1-[(2S,4R)-4-hydroxy]-2-[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)-ethylcarbamoyl]pyrrolidin-1-yl}-3,3-dimethyl-1-oxobutan-2-yl-carbamate(1.41 g, 74.2%) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.05 (s, 9H), 1.42 (s, 9H), 1.47 (d, J=7.2Hz, 3H), 2.04-2.10 (m, 1H), 2.53 (s, 3H), 2.58-2.64 (m, 1H), 3.23 (s,1H), 3.58 (dd, J=11.2 Hz, 3.2 Hz, 1H), 4.11 (d, J=11.6 Hz, 1H), 4.22 (d,J=9.2 Hz, 1H), 4.51 (br, 1H), 4.79 (t, J=8.0 Hz, 1H), 5.04-5.11 (m, 1H),5.22 (d, J=8.8 Hz, 1H), 7.36-7.42 (m, 4H), 7.61 (d, J=7.6 Hz 1H), 8.68(s, 1H).

This solid (1.04 g, 1.9 mmol) was dissolved in 4N hydrogen chloride inmethanol (3.0 mL) and the mixture was stirred at ambient temperature for3 hours. TLC showed reaction complete. The reaction mixture wasconcentrated to remove all volatiles under reduced pressure to give alight yellow solid. The solid was added to TBME (5 mL) and the resultingmixture was stirred at ambient temperature for 4 hours. The reactionmixture was filtered and the solid was collected and dried in oven at50° C. to afford the title compound (0.92 g, 100%).

¹H NMR (400 MHz, DMSO-d6): δ 1.03 (s, 9H), 1.38 (d, J=7.2 Hz, 3H),1.72-1.79 (m, 1H), 2.09-2.14 (m, 1H), 2.49 (s, 3H), 3.48-3.52 (m, 1H),3.75-3.79 (m, 1H), 3.88-3.90 (m, 1H), 4.31 (br, 1H), 4.56 (t, J=8.4 Hz,1H), 4.89-4.95 (m, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H),8.20 (br, 3H), 8.67 (d, J=7.6 Hz, 1H), 9.22 (s, 1H); ¹³C NMR (400 MHz,DMSO-d6): δ 170.7, 167.1, 153.0, 146.5, 145.7, 132.5, 129.4, 129.3,126.9, 69.4, 59.3, 58.5, 56.9, 48.3, 38.4, 34.8, 26.6, 23.0, 15.7; LC-MS[M+1]⁺: 445.6

Intermediate 3:(2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(ULM-3)

Step 1: Preparation of 2-hydroxy-4-(4-methylthiazol-5-yl) benzonitrile

A mixture of 4-bromo-2-hydroxybenzonitrile (15 g, 76 mmol),4-methylthiazole (14 mL, 152 mmol), KOAc (14.9 g, 152 mmol) and Pd(OAc)₂(0.34 g, 1.52 mmol) in dry NMP (125 mL) was stirred at 110° C. for 6hours under nitrogen atmosphere. TLC showed the reaction was complete.The mixture was first cooled to room temperature, then partitionedbetween EtOAc and water. The combined organic fraction was filtered andthe filtrate was washed with water, brine, dried over anhydrous Na₂SO₄,and concentrated. The residue was dissolved in toluene (100 mL) andre-evaporated to afford the crude product. The crude product was treatedwith cold MeOH (80 mL). The resulting precipitate was collected byfiltration, washed with MeOH (20 mL), and dried under vacuum to affordthe title compound as a light yellow solid (10.5 g, 64%).

LC/MS: 217.2 [M+1]⁺.

¹HNMR (400 MHz, DMSO-d6): δ2.49 (s, 3H), 7.07 (dd, J=8.0, 1.6 Hz, 1H),7.13 (d, J=1.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 9.07 (s, 1H), 11.34 (s,1H).

Step 2: Preparation of 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol

To a solution of 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (2.9 g,13.41 mmol) in dry THF (150 mL), was added LiAlH₄ (1.5 g, 40.23 mmol) inportions at 0° C. The resulting mixture was stirred at 50° C. for 3 hunder nitrogen atmosphere. TLC showed the reaction was complete. Themixture was cooled in ice-water bath then Na₂SO₄.10H₂O (5 g) was addedcarefully and stirred at this temperature for 1 h. The mixture wasfiltered and the filter cake was washed with 10% MeOH in DCM for fourtimes. The combined filtrates were concentrated to afford the crude2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol as a light yellow solid(2.0 g, 68%). It was used in next step without further purification.

LCMS: 221.2[M+H]⁺.

¹HNMR (400 MHz, DMSO-d6): δ2.43 (s, 3H), 3.54 (br, 2H), 6.11 (d, J=7.2Hz, 1H), 6.40 (d, J=11.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 8.81 (s, 1H).

Step 3: Preparation of (S)-3-methyl-2-(1-oxoisoindolin-2-yl) butanoicacid

L-Valine (4.37 g, 37.3 mmol) was added to a solution of phthalicdicarboxaldehyde (5.0 g, 37.3 mmol) in acetonitrile (350 mL). Theresulting mixture was refluxed for 5 hours. The reaction mixture wasfiltered whilst hot and the filtrate was cooled to room temperatureslowly. The resulting precipitate was filtered and dried to afford(S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid as a white solid(6.45 g, 74%).

¹HNMR (400 MHz, DMSO-d6): δ 0.85 (d, J=6.8 Hz, 3H), 1.0 (d, J=6.8 Hz,3H), 2.25-2.34 (m, 1H), 4.51 (d, J=4.4 Hz, 1H), 4.54 (d, J=3.6 Hz, 1H),4.64 (d, J=18.0 Hz, 1H), 7.48-7.54 (m, 1H), 7.63 (d, J=3.6 Hz, 2H), 7.72(d, J=7.6 Hz, 1H), 13.01 (br, 1H).

Step 4: Preparation of (2S,4R)-methyl4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate

To a solution containing 4-hydroxy-L-proline methyl ester hydrochloride(1.0 g, 5.52 mmol), (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid(1.16 g, 4.97 mmol), and DIPEA (2.58 g, 20 mmol) in dry DMF (15 mL) wasadded HATU (3.8 g, 10 mmol) at 0° C. The resulting mixture was stirredat room temperature for 2 hours. The mixture was partitioned betweenEtOAc and water. The organic phase was washed with water, brine anddried over anhydrous Na₂SO₄. The residue was purified by silica gelchromatography using 30-50% EtOAc in hexane as eluent to afford thetitle compound as a light yellow solid (1.21 g, 67.6%).

LCMS: 361.3[M+1]⁺.

Step 5: Preparation of(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylicacid

A mixture containing (2S,4R)-methyl4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate(1.2 g, 3.33 mmol), LiOH.H₂O (559 mg, 13.32 mmol) in THF (20 mL) and H₂O(10 mL) was stirred at room temperature for 2 hours. TLC showed thereaction was complete. The reaction mixture was acidified with 1N HCl topH 1-2, and extracted with EtOAc. The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated to afford the titlecompound as a light yellow solid (1.05 g, 91% yield).

¹HNMR (400 MHz, CDCl₃): δ0.91 (d, J=6.4 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H),2.30 (dd, J=8.4, 2.8 Hz, 2H), 2.44-2.50 (m, 1H), 3.75 (dd, J=11.2, 3.2Hz, 1H), 4.42 (d, J=17.6 Hz, 1H), 4.50-4.55 (m, 2H), 4.66 (t, J=8.4 Hz,1H), 4.75 (d, J=17.6 Hz, 1H), 4.83 (d, J=11.2 Hz, 1H), 7.42-7.45 (m,2H), 7.51-7.56 (m, 1H), 7.78 (d, J=7.6 Hz, 1H).

Step 6: Preparation of(2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide

To a solution containing(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylicacid (1.0 g, 2.89 mmol), 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol(954 mg, 4.33 mmol), and DIPEA (1.5 g, 11.55 mmol) in DMF (20 mL) wasadded HATU (2.2 g, 5.77 mmol) at 0° C. The resulting mixture was stirredat room temperature for 1 h. TLC showed the reaction was complete. Themixture was partitioned between EtOAc and water. The organic phase waswashed with water, brine and dried over anhydrous Na₂SO₄. The residuewas purified by silica gel column chromatography using 2-5% MeOH in DCMto afford the title compound as a light yellow solid (650 mg, 43%yield).

LCMS: 549.2[M+H]⁺

¹HNMR (400 MHz, CDCl₃): δ0.80 (d, J=6.8 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H),1.96-2.01 (m, 1H), 2.34-2.40 (m, 1H), 2.47-2.53 (m, 4H), 3.61 (dd,J=11.6, 3.6 Hz, 1H), 4.29-4.37 (m, 2H), 4.38-4.41 (m, 1H), 4.47-4.50 (m,2H), 4.64-4.69 (m, 2H), 4.72 (s, 1H), 6.90 (dd, J=8.0, 2.0 Hz, 1H), 7.01(d, J=2.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.39-7.44 (m, 2H), 7.51-7.54(m, 1H), 7.76 (d, J=7.6 Hz, 1H), 8.03 (t, J=6.4 Hz, 1H), 8.66 (s, 1H),9.27 (br, 1H).

Intermediate 4:(2R,4S)-1-[(S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N—[(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl]-pyrrolidine-2-carboxamidehydrochloride (ULM-4)

This compound was synthesized using the same method as descried in thepreparation of ULM-2 using (2R,4S)-methyl4-hydroxypyrrolidine-2-carboxylate hydrochloride. ¹HNMR (400 MHz,CD₃OD): δ 1.14 (s, 9H), 1.55 (d, J=6.8 Hz, 3H), 2.00-2.05 (m, 1H),2.51-2.58 (m, 1H), 2.65 (s, 3H), 3.77-3.81 (m, 1H), 3.88-3.92 (m, 1H),4.06 (br, 1H), 4.41-4.46 (m, 1H), 4.56-4.60 (m, 1H), 5.07-5.12 (m, 1H),7.58 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 10.02 (s, 1H). LC-MS[M+H]⁺: 445.3

Intermediate 5 and Intermediate 6:tert-butyl-N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate(ULM-5-A) and tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate(ULM-5-B)

Step 1: The synthesis of 2-(4-bromophenyl)oxirane

A mixture of 4-bromobenzaldehyde (2.52 g, 13.6 mmol), trimethylsulfoniumiodide (2.87 g, 14.1 mmol), water (0.65 mL, 36.1 mmol) and potassiumhydroxide (1.56 g, 27.7 mmol) in acetonitrile (20 mL) was warmed to 55°C. for 4 hours. The resulting solution was partitioned between water anddiethyl ether, and the organic layer was washed with water, dilutedhydrochloric acid, and brine, and dried over sodium sulfate. Crudeproduct of 2-(4-bromophenyl)oxirane (2.20 g, 81.8% yield) was obtainedby removal of organic solvent under reduced pressure, which was used fornext reaction without purification.

¹H NMR (400 MHz, CDCl₃) δ 2.74 (1H, q, J=2.8 Hz), 3.14 (1H, dd, J=4.0Hz, 5.2 Hz), 3.82 (1H, dd, J=2.4 Hz, 4.0 Hz), 7.15 (2H, d, J=8.4 Hz),7.47 (2H, d, J=8.8 Hz).

Step 2: The synthesis of 2-azido-2-(4-bromophenyl)ethanol

To a stirred suspension of 2-(4-bromophenyl)oxirane (5.0 g, 25.3 mmol)in distilled water (70 mL) was added the sodium azide (3.28 g, 50.5mmol), the resulting mixture was stirred at 60° C. for 4 hour and wasmonitored by TLC. After reaction completion, the mixture was extractedwith EtOAc, washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give2-azido-2-(4-bromophenyl)ethanol (5.5 g, 90.2%) as pale yellow oils. Thecrude product was used for next step directly.

¹H NMR (400 MHz, CDCl₃) δ 1.94 (1H, s), 3.63-3.66 (2H, m), 4.57 (1H, dd,J=5.2 Hz, 7.6 Hz), 7.15 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.4 Hz).

Step 3: The synthesis of 2-amino-2-(4-bromophenyl)ethanol hydrochloride

To a solution of 2-azido-2-(4-bromophenyl)ethanol (2.0 g, 8.30 mmol) intetrahydrofuran (20.0 mL) and water (5.00 mL) was addedtriphenylphosphine (4.35 g, 16.6 mmol). The reaction mixture was stirredat room temperature overnight and the solvent was removed in vacuo. Theresidue was dissolved in HCl/dioxane (4M, 10.0 mL) and stirred at roomtemperature for 1 hour. After being concentrated, the solid was washedwith dichloromethane to give 2-amino-2-(4-bromophenyl)ethanolhydrochloride (1.5 g, 72.1% yield) as white solids.

¹H NMR (400 MHz, CDCl₃) δ 3.70 (2H, s), 4.28 (1H, s), 5.55 (1H, s), 7.47(2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz), 8.61 (3H, s); LC/MS 216.2[M+H]⁺.

Step 4: The synthesis of1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanamine

To a solution of 2-amino-2-(4-bromophenyl)ethanol hydrochloride (1.80 g,7.17 mmol) in dichloromethane (50 mL) was added imidazole (1.95 g, 2.87mmol) and tert-butyldimethylsilyl chloride (TBSCl) (1.63 g, 10.8 mmol)are room temperature. The reaction mixture was stirred at roomtemperature overnight and then quenched with water. The aqueous phasewas extracted with dichloromethane (30 mL×3), the combined organicphases were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give crude compound. The crude product waspurified by silica gel column chromatography (petroether/ethylacetate=5:1) to give1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanamine (1.50 g,63.6%) as white solids.

LC/MS: 330.1 [M+H]⁺;

Step 5: The synthesis of tert-butyl1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate

To a solution of1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanamine (1.50 g, 4.56mmol) in tetrahydrofuran (20 mL) was added triethylamine (0.69 g, 6.84mmol) and di-tert-butyl dicarbonate (1.49 g, 6.84 mmol). The reactionmixture was stirred at room temperature overnight and then quenched withwater. The aqueous phase was extracted with ethyl acetate (50 mL×3) andwashed with brine. The combined organic phases were dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to give crudecompound. The crude product was purified by silica gel columnchromatography (petroether/ethyl acetate=100:1) to give tert-butyl1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate (1.80 g,92.0%) as pale yellow oils.

¹H NMR (400 MHz, CDCl₃) δ 0.01 (6H, d, J=9.6 Hz), 0.86 (9H, s), 1.42(9H, s), 3.65-3.70 (2H, m), 4.60-4.63 (1H, m), 7.34 (2H, d, J=8.0 Hz),7.39 (1H, d, J=8.8 Hz), 7.56 (2H, d, J=8.4 Hz).

Step 6: The synthesis of tert-butyl2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)-ethylcarbamate

A mixture of tert-butyl1-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)ethylcarbamate (4.0 g,9.32 mmol), 4-methylthiazole (1.85 g, 18.6 mmol), potassium acetate(1.82 g, 18.6 mmol), palladium (II) acetate (0.11 g, 0.47 mmol) weredissolved in dimethylacetamide and stirred under argon. The mixture washeated to 140° C. and stirred for 15 hours, then diluted with water. Theaqueous phase was extracted with ethyl acetate (50 mL×3) and washed withbrine. The combined organic layer was dried over sodium sulfate,filtered and concentrated under vacuum to give crude compound which waspurified by silica gel column chromatography (petroether/ethylacetate=100:1) to give tert-butyl2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl) ethylcarbamate (1.30 g,41.8%) as pale yellow solids.

¹H NMR (400 MHz, CDCl₃) δ 1.38 (9H, s), 2.46 (3H, s), 3.52 (2H, t, J=6.0Hz), 4.55-4.58 (1H, m), 4.84 (1H, t, J=6.0 Hz), 7.30 (1H, d, J=8.0 Hz),7.38-7.45 (4H, m), 8.99 (1H, s); LC/MS 335.2 [M+H]⁺; Rt=1.859 min

Step 7: The synthesis of2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride

The tert-butyl2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamate (300 mg,0.536 mmol) was dissolved in hydrochloric acid/dioxane (5 mL, 4M). Theresulting reaction mixture was stirred at room temperature for 3 hours.The solvent was concentrated in vacuo to give2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanol hydrochloride as whitesolids, which was used for the next step without further purification.

Step 8: The synthesis of tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate(ULM-5-A) and tert-butylN-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate(ULM-5-B)

A solution of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethanolhydrochloride (1000 mg, 3.70 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (995mg, 5.19 mmol), 1-hydroxybenzotriazole (HOBT) (695 mg, 5.19 mmol),(2S,4R)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylicacid (1273 mg, 3.70 mmol) and triethylamine (747 mg, 7.40 mmol) inN,N-dimethylformamide (50 mL) was stirred at room temperature overnightunder argon, and then water (80 mL) was added to the mixture. Theaqueous layer was extracted with ethyl acetate (50 mL×5). The combinedorganic layer was washed with brine (50 mL×3), dried over anhydroussodium sulfate, and concentrated in vacuo. The crude product waspurified by preparative TLC (dichloromethyl/methanol=15:1) to givetert-butyl(S)-1-((2S,4R)-4-hydroxy-2-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate(700 mg) as pale yellow oils and tert-butyl(S)-1-((2S,4R)-4-hydroxy-2-((S)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate(500 mg) as pale yellow oils.

ULM-5-A: ¹H NMR (400 MHz, CDCl₃) δ 0.93 (9H, s), 1.39 (9H, s), 1.77-1.83(1H, m), 2.01-2.06 (1H, m), 2.46 (3H, s), 3.54-3.60 (4H, m), 4.13-4.19(1H, m), 4.29-4.36 (1H, m), 4.50 (1H, t, J=8.0 Hz), 4.78 (1H, t, J=5.6Hz), 4.81-4.88 (1H, m), 5.12-5.16 (1H, m), 6.46 (1H, d, J=9.2 Hz),7.36-7.46 (4H, m), 8.41 (1H, d, J=8.0 Hz), 8.99 (1H, s); LC/MS 561.2[M+H]⁺; Rt=1.897 min

ULM-5-B: ¹H NMR (400 MHz, CDCl₃) δ 0.87 (9H, s), 1.38 (9H, s), 1.92-2.06(2H, m), 2.45 (3H, s), 3.56-3.69 (4H, m), 4.06-4.14 (1H, m), 4.36 (1H,s), 4.56 (1H, t, J=7.6 Hz), 4.76-4.81 (1H, m), 4.87 (1H, t, J=5.6 Hz),5.146 (1H, d, J=2.8 Hz), 6.47 (1H, d, J=8.8 Hz), 7.37 (2H, d, J=8.0 Hz),7.51 (2H, d, J=8.0 Hz), 8.37 (1H, d, J=7.6 Hz), 8.98 (1H, s); LC/MS561.2 [M+H]⁺; Rt=1.887 min

Intermediate 7:(2S,4R)—N-[(4-chloro-2-hydroxyphenyl)methyl]-4-hydroxy-1-[3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide(ULM-6)

This key intermediate was prepared using the synthetic route above. Therequired 3-methylisoxazole-5-acetic acid was prepared according to theliterature (J. Org. Chem. 66, 6595-6603, 2001). The alkylation with2-iodopropane has been described in the literature. The desired ULM-6was prepared using the same synthetic method as described in thepreparation of intermediate ULM-3.

¹H NMR (400 MHz, CDCl₃): δ 9.33 (s, 0.5H), 9.20 (s, 0.5H), 8.07 (t,J=6.4 Hz, 0.5H), 7.83 (t, J=6.0 Hz, 0.5H), 6.99 (dd, J=2.4, 8.0 Hz, 1H),6.89-6.90 (m, 1H), 6.76-6.78 (m, 1H), 6.02 (s, 0.5H), 5.99 (s, 0.5H),5.80-5.83 (m, 0.5H), 4.35 (q, J=6.4 Hz, 1.5), 4.16-4.25 (m, 2H),3.72-3.76 (m, 0.5H), 3.61 (d, J=9.2 Hz, 1.0H), 3.51-3.55 (m, 1.5H),2.30-2.46 (m, 2.5H), 2.26 (s, 1.5H), 2.24 (s, 1.5H), 1.95-2.05 (m, 1H),1.01 (d, J=6.8 Hz, 1.5H), 0.82-0.87 (m, 4.5H); LC-MS 436.1 [M+1]⁺;Rt=3.57 min.

PTM Synthesis:

Preferred PTM embodiments of the current disclosure can be preparedaccording to the synthetic routes in schemes 1-3 below. These routes canbe modified and adapted to the synthesis of the particular PTMembodiment using general methods known to those skilled in the art.

Exemplary PROTAC Synthesis: Intermediate 1

Step 1:2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 1.82mmol) in DMF (10 mL) were added K₂CO₃ (756 mg, 5.47 mmol) and2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methyl-benzenesulfonate (832 mg,2.73 mmol) at 25° C. The resulting solution was stirred at 70° C. for 5hours. After cooling to room temperature, the reaction was quenched withH₂O (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified with silica gel column to affordthe desired product (95 mg, 13% yield).

Step 2:2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)acetaldehyde

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)isoindoline-1,3-dione(95 mg, 0.23 mmol) in CH₃CN (5 mL) was added IBX (130 mg, 0.46 mmol) at25° C. The reaction was stirred at 80° C. for 2 hours. After cooling toroom temperature, the mixture was filtered through Celite, and thefiltrate was concentrated to afford crude intermediate 1,2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)acetaldehyde,(90 mg), which was used without further purification.

Intermediate 2

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (10 g, 36.2mmol) in NMP (70 mL) was added tert-butyl piperazine-1-carboxylate(13.47 g, 72.5 mmol) and DIPEA (18.6 g, 14.5 mmol). The resultingmixture was stirred at 90° C. for 16 hours. After cooling to roomtemperature, the reaction was quenched with water (100 mL), and themixture was extracted with ErOAc (300 mL×2). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE/EA=100-2/1) to afford the desired product,2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (14g, 31.67 mmol, 87.5% yield) as a light yellow solid.

Synthetic Scheme for Exemplary Compound 51

Step 1: 3-(4-bromophenyl)-4-nitropyridine

To a stirred solution of 3-bromo-4-nitropyridine (100 g, 492.6 mmol),(4-bromophenyl)boronic acid (98.6 g, 492.6 mmol), and potassiumcarbonate (203.9 g, 1.47 mol) in toluene (1000 ml)-water (100 ml) wasadded tetrakis(triphenylphosphine)palladium (14.8 g, 12.8 mmol) at roomtemperature under nitrogen atmosphere; the mixture was degassed withnitrogen three times. The resulting mixture was stirred at 50° C.overnight. TLC showed the reaction was complete. The solid was removedthrough filtration and washed with ethyl acetate (100 ml×3). The organiclayer was collected and the aqueous layer was extracted with ethylacetate (100 ml×2). The combined organic layers were washed with brine(400 ml), dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give a crude residue which was purified by silicagel pad (eluted with 10-33% ethyl acetate in hexane) to afford3-(4-bromophenyl)-4-nitropyridine (89 g, yield 65%) as yellow solid.

Step 2: 7-bromo-5H-pyrido[4,3-b]indole

A mixture of 3-(4-bromophenyl)-4-nitropyridine (20.0 g, 71.7 mmol) intriethyl phosphate (400 ml) was stirred at 110° C. for 2 hours undernitrogen atmosphere. TLC showed the reaction was complete. The volatileswere evaporated under reduced pressure to give a residue which waspurified by recrystallization (methanol) to afford7-bromo-5H-pyrido[4,3-b]indole (11.0 g, yield 62%) as brown solid.

Step 3: 7-(6-Fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole

A mixture of 7-bromo-5H-pyrido[4,3-b]indole (400 mg, 1.63 mmol),(6-fluoropyridin-3-yl)boronic acid (344 mg, 2.44 mmol), PdCl₂(dppf) (120mg, 0.163 mmol), tBu₃PHBF₄ (95 mg, 0.326 mmol) and Cs₂CO₃ (1.1 g, 3.26mmol) in dioxane/water (20 mL, 20:1) was heated to 90° C. for 4 hoursunder N2. The solid was filtered and the filtrate was evaporated. Theresidue was purified by chromatography (silica gel, 200-300 mesh,CH₂Cl₂: MeOH=30:1) to afford7-(6-Fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (250 mg, 59% yield).

Step 4:14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol

To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (270 mg, 1.13mmol) in THF (10 mL) was added NaH (45 mg, 60%, 1.13 mmol) at 0° C.After stirring at 20° C. for 1 hour, a solution of7-(6-Fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (150 mg, 0.57 mmol) inDMF (2.0 mL) was added. The resulting solution was stirred at 80° C. for4 hours. After cooling to room temperature, the reaction was dilutedwith EA (30 mL), and the mixture was washed with brine. The organicphase was evaporated under reduced pressure. The residue was purified bysilica gel column chromatography on silica gel (DCM/MeOH=4/1) to affordthe desired product (200 mg. 72.89% yield) as a colorless oil.

Step 5: tert-butyl7-(6-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

To a solution of14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol(150 mg, 0.31 mmol) in DCM (10 mL) were added NEt₃ (94.5 mg, 0.93 mmol)and Boc₂O (102.0 mg, 0.47 mmol). The resulting solution was stirred atambient temperature for 12 hours. The solvent was removed under vacuum.The residue was diluted with EA (30 mL), and the mixture was washed withbrine. The organic phase was dried over anhydrous sodium sulfate, andconcentrated in vacuo to afford the desired product (120 mg, 66% yield),which was used in the next step without further purification.

Step 6: tert-butyl7-(6-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

To a solution of tert-butyl7-(6-((14-hydroxy-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate(120 mg, 0.31 mmol) and NEt₃ (93.9 mg, 0.93 mmol) in DCM (10 mL) wasadded MsCl (38.9 mg, 0.34 mmol) at 0° C. After stirring at 30° C. for 1hour, the solvent was removed. The residue was diluted with EA (30 mL),and washed with brine. The organic phase was concentrated to give theintermediate mesylate.

To the stirred solution of mesylate (100 mg, 0.15 mmol) in dry DMF (10mL) were added2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (45.6 mg,0.17 mmol) and K₂CO₃ (31.4 mg, 0.23 mmol). The resulting mixture wasstirred at 68° C. for 4 hours. The mixture was diluted by EtOAc (40 mL),washed with brine twice, and dried over anhydrous sodium sulfate. Theorganic phase was evaporated under reduced pressure. The residue waspurified by prep-TLC (DCM/MeOH=20/1) to afford the desired product as ayellow solid (15 mg, 23.6% yield).

Step 7:5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of tert-butyl7-(6-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate(30 mg, 0.036 mmol) in DCM (2 mL) was added TFA (5 mL). The mixture wasstirred at ambient temperature for 4 hours. The mixture was evaporatedunder reduced pressure. The residue was purified by prep-HPLC to affordthe title compound as a white solid (10 mg, 38% yield). ¹H NMR (400 MHz,CDCl₃): δ 12.34-12.48 (m, 1H), 9.19-9.29 (m, 1H), 8.80 (s, 1H),8.29-8.42 (m, 1H), 8.02-8.14 (m, 1H), 7.95 (s, 1H), 7.69-7.81 (m, 1H),7.60 (s, 2H), 7.17 (s, 1H), 7.09 (s, 1H), 6.62 (s, 1H), 4.97 (s, 1H),4.43 (s, 2H), 4.14 (s, 2H), 3.88 (d, J=24.1 Hz, 3H), 3.78 (d, J=8.2 Hz,3H), 3.69 (d, J=10.0 Hz, 6H), 2.80 (m, 4H), 1.99-2.29 (m, 4H). (M+H)⁺738.3.

Using procedures analogous to those for Compound 51, Compound 50 wasalso prepared.

Synthetic Scheme for Exemplary Compound 52

Step 1: tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate

The solution of 2-(piperazin-1-yl)ethanol (5 g, 38.5 mmol) and TEA (12g, 115 mmol) was stirred in DCM at 0° C., Boc₂O was added, then themixture was stirred at 10° C. overnight. Water was added. Then themixture was extracted with DCM, dried and concentrated, and filteredthrough a silica gel pad to get 8.1 g product (92% yield).

Step 2: tert-butyl4-(2-(prop-2-yn-1-yloxy)ethyl)piperazine-1-carboxylate

The solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (3g, 13 mmol) in THF was stirred at 0° C. NaH (624 mg, 15.6 mmol) wasadded, then, the mixture was stirred at room temperature for 1 hour.3-bromoprop-1-yne (1.85 g, 15.6 mmol) was added, and stirring wascontinued at 70° C. overnight. Then the mixture was cooled to roomtemperature. Water was added, then the mixture was extracted with EA,dried with Na₂SO₄ and concentrated. Filtered through a silica gel pad(EA) to get 1.5 g product (43% yield).

Step 3: tert-butyl4-(2-((3-(5-bromopyridin-2-yl)prop-2-yn-1-yl)oxy)ethyl)piperazine-1-carboxylate

tert-butyl 4-(2-(prop-2-yn-1-yloxy)ethyl)piperazine-1-carboxylate (500mg, 1.86 mmol), 2,5-dibromopyridine (442 mg, 1.86 mmol), Pd(PPh₃)₂Cl₂(10%), CuI (11%), DIPEA and CH₃CN were stirred at 5° C. overnight, andEA was added. The mixture was washed by water, concentrated. Thenfiltered through a silica gel (EA) to get 450 mg product (57% yield).

Step 4: tert-butyl4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazine-1-carboxylate

7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole-5-carboxylate[prepared by using procedure analogous to that of step 1 of ExemplaryCompound 63] (300 mg, 0.76 mmol), Pd(aMphose)Cl₂ (50 mg, 10%), and CsF(450 mg, 2.96 mmol) was stirred in CH₃CN/H₂O (10:1) at 120° C. in themicrowave for 40 minutes. The mixture was cooled to room temperature,and EA was added. The organic layer was washed by water, then filteredthrough a silica gel pad (DCM:MeOH=20:1) to get 100 mg tert-butyl4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-ynyloxy)ethyl)piperazine-1-carboxylate.The crude product was dissolved in MeOH, Pd/C was added, and the mixturewas stirred at 30° C. under 2 Mpa of H₂ for 2 hours, filtered andconcentrated to produce 100 mg of product (26% yield).

Step 5:7-(6-(3-(2-(piperazin-1-yl)ethoxy)propyl)pyridin-3-yl)-5H-pyrido[4,3-b]indole

tert-butyl4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazine-1-carboxylate(100 mg, 0.2 mmol) in HCl/dioxane solution (2 mL) was stirred at 5° C.for 1 hour. Concentrated to obtain 100 mg of crude product.

Step 6:5-((5-(4-(2-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)pentanal (86mg, 0.24 mmol), NaBH₄CN (55 mg, 0.48 mmol) and CH₃COOH (cat.) wasstirred in MeOH at 5° C. for 3 hours. Then DCM added. The organic layerwas washed by water, concentrated, and filtered through silica gel pad(DCM:MeOH=8:1) to afford 11 mg of product.

¹HNMR (400 MHz, MeOD): δ 9.25 (s, 1H), 8.79 (s, 1H), 8.37-8.39 (d, J=8Hz, 1H), 8.28-8.30 (d, J=8 Hz, 1H), 8.11-8.13 (d, J=8 Hz, 1H), 7.80 (s,1H), 7.75-7.77 (d, J=8 Hz, 1H), 7.60 (s, 1H), 7.49-7.51 (d, J=8 Hz, 1H),7.43-7.45 (d, J=8 Hz, 1H), 7.33 (s, 1H), 5.07-5.09 (m, 1H), 4.06-4.09(m, 2H), 3.57-3.60 (m, 2H), 3.51-3.54 (m, 2H), 2.93-2.95 (m, 2H),2.91-2.93 (m, 1H), 2.59-2.75 (m, 12H), 2.37-2.41 (m, 2H), 2.04-2.06 (m,3H), 1.78-1.80 (m, 2H), 1.46-1.55 (m, 5H). (M+H)⁺ 758.3.

Synthetic Scheme for Exemplary Compound 53

Step 1: (((1s, 3s)-3-(allyloxy)cyclobutoxy)methyl)benzene

To a solution of (is, 3s)-3-(benzyloxy)cyclobutanol (1.0 g, 5.61 mmol)in DMF (10 mL) was added NaH (60%, 0.336 g, 8.4 mmol) at 0° C. Afterstirring for 30 min, 3-bromoprop-1-ene was added dropwise at roomtemperature. The resulting solution was stirred at room temperature for3 hours. After it was quenched with saturated solution NH₄Cl (20 mL),the mixture was extracted with EtOAc (20 mL×2). The combined organiclayers were dried with Na₂SO₄ and concentrated under vacuum. The residuewas purified by silica gel column with PE/EA=10-1: as eluent to affordthe desired product (1.0 g, 82%) as a colorless oil.

Step 2: 3-((1s, 3s)-3-(benzyloxy)cyclobutoxy)propan-1-ol

To a solution of (((1s, 3s)-3-(allyloxy)cyclobutoxy)methyl)benzene (1.0g, 4.58 mmol) in THF (20 mL) was added dicyclohexylborane in THF (1.0 M,9.0 mL) at 0° C. After it was stirred at room temperature for 4 hours,NaOH (37%, 3.0 mL) and H₂O₂ (30%, 3.0 mL) were added to the mixture at0° C. The resulting solution was stirred at room temperature overnight.The reaction was quenched with Na₂S₂O₃ (20 mL). The mixture was taken upin DCM. The organic phase was dried with Na₂SO₄ and concentrated undervacuum. The residue was purified on silica gel column with PE/EA=2:1 aseluent to afford the desired product (1.0 g, 100%) as a colorless oil.

Step 3: tert-butyl 4-(3-((1s,3s)-3-(benzyloxy)cyclobutoxy)propyl)piperazine-1-carboxylate

To a solution of 3-((1s, 3s)-3-(benzyloxy)cyclobutoxy)propan-1-ol (1.0g, 4.58 mmol) and TEA (2.0 g, 19.8 mmol) in DCM (10 mL) was added MsCl(0.97 g, 9.2 mmol) at 0° C. After stirring at room temperature for 2hours, the reaction was quenched with saturated solution of sodiumbicarbonate (20 mL), and the mixture was extracted DCM (20 mL×2). Thecombined organic layers were dried with Na₂SO₄, and concentrated undervacuum to afford the desired product (1.1 g, crude), which was used inthe next reaction without further purification.

To a solution of the above intermediate (1.1 g, crude) in DMF (10 mL)was added tert-butyl piperazine-1-carboxylate (1.60 g, 9.2 mmol). Theresulting solution was heated to 90° C. for 4 hours. After cooling toroom temperature, the reaction was quenched with water (20 mL) and themixture was extracted with EtOAc (20 mL×3). The combined organic layerswere dried over Na₂SO₄, and concentrated under vacuum. The residue waspurified by silica gel column with PE/EA=2:1 as eluent to afford thedesired product (980 mg, 58%) as a colorless oil.

Step 4: tert-butyl 4-(3-((1s,3s)-3-hydroxycyclobutoxy)propyl)piperazine-1-carboxylate

A mixture of tert-butyl 4-(3-((1s,3s)-3-(benzyloxy)cyclobutoxy)propyl)piperazine-1-carboxylate (980 mg,2.42 mmol) and Pd(OH)₂/C (300 mg, 20%) in CH₃OH (10 mL) was stirred atroom temperature overnight under H₂ at 1 atm. The mixture was filteredthrough Celite, and the filtrate was concentrated to afford the desiredproduct (700 mg, crude) which was used in the next reaction withoutfurther purification.

Step 5: tert-butyl 4-(3-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(3-((1s,3s)-3-hydroxycyclobutoxy)propyl)piperazine-1-carboxylate (180 mg, 0.57mmol) and 7-(6-Fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (100 mg, 0.379mmol) in NMP (10 mL) was added NaH (60%, 100 mg, 2.5 mmol) at roomtemperature. The resulting solution was heated to 90° C. for 2 hours.After cooling to room temperature, the reaction was quenched withsaturated solution of NH₄Cl (20 mL), and the mixture was extracted withEtOAc (20 mL×3). The combined organic layers were dried with Na₂SO₄ andconcentrated under vacuum. The residue was purified by prep-TLC withDCM/CH₃OH (15:1) to afford the desired product (120 mg, 0.21 mmol) as abrown solid.

Step 6: 7-(6-((1s,3s)-3-(3-(piperazin-1-yl)propoxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

A mixture of tert-butyl 4-(3-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazine-1-carboxylate(120 mg, 0.21 mmol) in CH₃OH (2.0 mL) and HCl in 1,4-dioxane (4.0 mL)was stirred at room temperature for 2 hours. The solvent was removedunder vacuum to afford the desired product (100 mg, crude), which wasused in the next reaction without further purification.

Step 7: 5-(4-(3-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a mixture of 7-(6-((1s,3s)-3-(3-(piperazin-1-yl)propoxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(80 mg, crude) and DIEA (300 mg, 2.36 mmol) in NMP (2.0 mL) was added2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (100 mg, 0.36mmol). The mixture was microwave heated at 130° C. for 45 minutes. Aftercooling to room temperature, the reaction was taken up with EtOAc (100mL). The mixture was washed with brine (20 mL×3). The organic phase wasdried with Na₂SO₄, and concentrated under vacuum. The residue waspurified by prep-TLC with DCM/CH₃OH/NH₃H₂O (15:1:0.1) to afford thetitle product (16.0 mg, 13%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 9.34 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.44(m, 2H), 8.20 (d, J=8.4 Hz, 1H), 7.87-7.92 (m, 3H), 7.68 (d, J=8.4 Hz,1H), 7.60 (s, 1H), 7.48-7.50 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.06 (m,1H), 6.84 (d, J=8.8 Hz, 2H), 4.93-4.94 (m, 2H), 3.75 (m, 2H), 3.42-3.49(m, 6H), 2.72-2.98 (m, 5H), 2.61 (s, 4H), 2.53 (t, J=7.2 Hz, 2H),2.15-2.18 (m, 2H), 1.81 (t, J=6.8 Hz, 2H). (M+H)⁺ 714.3

Synthetic Scheme for Exemplary Compound 55

Step 1: tert-butylI-4-(5-(3-methoxy-3-oxoprop-1-en-1-yl)pyridin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-formylpyridin-2-yl)piperazine-1-carboxylate (1.0 g, 3.44 mmol) andmethyl 2-(dimethoxyphosphoryl)acetate (750 mg, 4.12 mmol) in THF (15 ml)was added DBU (1.57 g, 10.3 mmol). The reaction mixture was stirred atroom temperature overnight. After it was quenched with water H₂O (10mL), the mixture was extracted with ethyl acetate (50 mL). The organicphase was washed with brine, and dried over Na₂SO₄. It was filtered, andconcentrated under vacuum. The residue was broken with petroleum etherto afford the desired product (800 mg, 2.3 mmol, yield: 66.9%) as a palesolid.

Step 2: tert-butyl4-(5-(3-hydroxypropyl)pyridin-2-yl)piperazine-1-carboxylate

To a solution of tert-butylI-4-(5-(3-methoxy-3-oxoprop-1-en-1-yl)pyridin-2-yl)piperazine-1-carboxylate

(800 mg, 2.3 mmol) in CH₃OH (8 mL) and THF (35 mL) was added NaBH₄ (874mg, 23.0 mmol). The mixture was heated to 80° C. for 3 hours. Aftercooling to room temperature, the reaction was quenched with 2N NH₄Cl,and the mixture was extracted with EtOAc (80 mL×3). The combined organiclayers were washed with brine, and dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by silicagel column (EA:PE=1:1) to give the desired compound (420 mg, 1.31 mmol,yield: 57.0%) as a yellow oil.

Step 3: tert-butyl4-(5-(3-((methylsulfonyl)oxy)propyl)pyridin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-(3-hydroxypropyl)pyridin-2-yl)piperazine-1-carboxylate (50 mg, 0.16mmol) and Et₃N (48 mg, 0.48 mmol) in DCM (2 mL) was added MsCl (27 mg,0.23 mmol). The reaction was stirred at room temperature for 1 hour.After it was quenched with water H₂O (30 mL), the mixture was extractedwith DCM (20 mL). The organic phase was washed with brine, dried overNa₂SO₄, filtered, and concentrated under vacuum to give the crudedesired compound (64 mg) as a yellow oil which was used in the nextreaction without further purification.

Step 4: tert-butyl4-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)pyridin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-(3-((methylsulfonyl)oxy)propyl)pyridin-2-yl)piperazine-1-carboxylate(64 mg, 0.16 mmol) and2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (66 mg, 0.24mmol) in DMF (5 ML) was added K₂CO₃ (55 mg, 0.40 mmol). The reactionmixture was stirred at 90° C. for 2 hours. After cooling to roomtemperature, the reaction was quenched water (5 mL), and the mixture wasextracted with dichloromethane (30 mL). The organic phase was washedwith water and brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by silica gel column(MeOH:DCM=1:100-1:20) to give the title product (30 mg, 0.052 mmol,yield: 32%).

Step 5:2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-(piperazin-1-yl)pyridin-3-yl)propoxy)isoindoline-1,3-dione

To a solution of tert-butyl4-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)pyridin-2-yl)piperazine-1-carboxylate(200 mg, 0.39 mmol) in dioxane (10 mL) was added 6N HCl in dioxane (2mL, 12.0 mmol). The reaction mixture was stirred at room temperature for2 hours. The solvent was removed under reduced pressure to give thecrude title product (200 mg) as a yellow solid.

Step 6: (6-(3-Hydroxyprop-1-yn-1-yl)pyridin-3-yl)boronic acid

To a solution of (6-bromopyridin-3-yl)boronic acid (1.0 g, 4.95 mmol)and prop-2-yn-1-ol (830 mg, 14.8 mmol) in THF (30 mL) were addedPdCl₂(PPh₃)₂ (350 mg, 0.50 mmol), ^(i)Pr₂NH (2 g, 19.8 mmol) and CuI (95mg, 0.5 mmol). The reaction mixture was stirred at room temperatureovernight. The mixture was filtered through Celite, and to the filtratewas added 1N NaOH (10 mL). The mixture was extracted with DCM. The pHwas adjusted to around 6 with 2N HCl. The aqueous solution was extractedwith ethyl acetate. The combined EtOAc layers were dried over Na₂SO₄,filtered, and evaporated to dryness under reduced pressure to give thedesired compound (500 mg, 2.82 mmol, yield 57%) as a pale solid.

Step 7: 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-yn-1-ol

To the mixture of 7-bromo-5H-pyrido[4,3-b]indole (50 mg, 0.20 mmol) and(6-(3-Hydroxyprop-1-yn-1-yl)pyridin-3-yl)boronic acid (53 mg, 0.30 mmol)in dioxane (10 mL) and water (1.0 mL) were added PdCl₂(dppf) (29 mg,0.04 mmol), Cs₂CO₃ (130 mg, 0.40 mmol) and ^(t)Bu₃PHBF₄ (23 mg, 0.08mmol). The mixture was stirred at 100° C. for 3 hours under N2atmosphere. After cooling to room temperature, the reaction was quenchedwith water (3 mL), and the mixture was extracted with EtOAc (20 ml×3).The combined organic layers were washed with brine, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified on silica gel column (MeOH:DCM=1:20-1:10) to give the desiredcompound (30 mg, 0.10 mmol, yield: 50.0%) as a yellow solid.

Step 8: 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol

To a solution of3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-yn-1-ol (30 mg,0.10 mmol) in MeOH (2 mL) was added Pd(OH)₂/C (20%, 10 mg) and cat.Conc. HCl (0.1 mL). The reaction was stirred at room temperature for 2hours under H₂ atmosphere. The mixture was filtered through Celite, andthe filtrate was concentrated to give the crude desired compound (30 mg)as a yellow oil.

Step 9: 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propanal

A solution of 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol(100 mg, 0.33 mmol) in DMSO (4 mL) was mixed with IBX (231 mg, 0.82mmol). The reaction mixture was stirred at 25° C. for 2 hours. Thereaction was quenched with saturated Na₂S₂O₃ (2 mL) and saturated NaHCO₃(2 mL). The mixture was extracted with dichloromethane (30 mL). Theorganic phase was washed with water and brine. It was dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give the crudetitle product (60 mg) as a yellow oil.

Step 10:5-(3-(6-(4-(3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pyridin-3-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of 3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propanal(100 mg, crude) in MeOH (10 mL) were added2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-(piperazin-1-yl)pyridin-3-yl)propoxy)isoindoline-1,3-dione(100 mg, 0.21 mmol) and NaBH₃CN (41 mg, 0.66 mmol). The reaction mixturewas stirred at room temperature for 1 hour. The mixture was diluted withwater (6 ml) and extracted with DCM (20 mL×2). The combined organiclayers were washed with water and brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified byprep-HPLC to give the desired product (15 mg, 0.02 mmol) as a whitesolid.

¹H NMR (400 MHz, MeOD): δ 9.62 (s, 1H), 9.03 (s, 1H), 8.58 (d, J=6.8 Hz,1H), 8.52 (d, J=8.0 Hz, 1H), 8.31-8.40 (m, 1H), 8.08 (s, 1H), 7.87-7.99(m, 2H), 7.78-7.87 (m, 3H), 7.68-7.72 (m, 1H), 7.26-7.30 (m, 2H),7.10-7.14 (m, 1H), 5.08-5.12 (m, 1H), 4.17 (t, J=6.0 Hz, 2H), 3.81-3.92(m, 4H), 3.50-3.60 (m, 4H), 3.30-3.40 (m, 2H), 3.10-3.18 (m, 2H),2.71-2.86 (m, 5H), 2.30-2.33 (m, 2H), 2.10-2.16 (m, 3H). (M+H)⁺ 763.3

Synthetic Scheme for Exemplary Compound 56

5-((5-(4-(2-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: (1s, 3s)-3-(benzyloxy)cyclobutan-1-ol

To a solution of 3-(benzyloxy)cyclobutanone (10.0 g, 56.75 mmol) in EtOH(100 mL) was added NaBH₄ (4.3 g, 68.1 mmol) at 0° C. The mixture wasstirred at 10° C. for 2 hours. After the reaction was quenched with 10%NH₄Cl, the mixture was extracted with ethyl acetate (200 mL). Thecombined organic layers were washed with brine (150 mL), dried overanhydrous sodium sulfate and concentrated under vacuum to give crude thedesired product (9.5 g) as a colorless oil, which was used in the nextstep without further purification.

Step 2: (((1s, 3s)-3-(2,2-diethoxyethoxy)cyclobutoxy)methyl)benzene

To a solution of (1s, 3s)-3-(benzyloxy)cyclobutan-1-ol (300 mg, crude,1.69 mmol) in THF (10 mL) was added NaH (168 mg, 4.22 mmol, 60%). Afterstirring at 5° C. for 0.5 hours, 2-bromo-1,1-diethoxyethane (333 mg,3.38 mmol) was added. The resulting mixture was stirred at 70° C. for 18hours. After cooling to room temperature, the reaction was diluted withwater (50 mL), and the mixture was extracted with EA. The organic phasewas washed with brine, dried over MgSO₄, and concentrated. The residuewas purified by chromatography (silica gel, PE:EA (50:1, v:v)) to affordthe desired compound (220 mg) as a yellow solid.

Step 3: 2-((1s, 3s)-3-(benzyloxy)cyclobutoxy)acetaldehyde

To a solution of (((1s,3s)-3-(2,2-diethoxyethoxy)cyclobutoxy)methyl)benzene (220 mg, 0.74 mmol)in CH₃CN (5 mL) was added HCl (2 mL, 2.5 mol/L in H₂O). The resultingmixture was stirred at 70° C. for 2 hours. TLC (PE:EA=3:1, Rf=0.5)showed that starting material was consumed. The mixture was diluted withwater (50 mL) and extracted with EA. The organic phase was washed withNaHCO₃, brine. The solution was dried over MgSO₄ and concentrated toafford the desired compound (170 mg, crude) as a yellow oil, which wasused in the next step without further purification.

Step 4: tert-butyl 4-(2-((1s,3s)-3-(benzyloxy)cyclobutoxy)ethyl)piperazine-1-carboxylate

To a solution of 2-((1s, 3s)-3-(benzyloxy)cyclobutoxy)acetaldehyde (170mg, crude, 0.772 mmol) in MeOH (10 mL) were added tert-butylpiperazine-1-carboxylate (215 mg, 1.16 mmol), AcOH (1 drop) and NaBH₃CN(97 mg, 154 mmol). The resulting mixture was stirred at 10° C. for 18hours. The reaction mixture was diluted with water (50 mL) and themixture was extracted with EA. The organic phase was washed with brine,dried over MgSO₄, and concentrated. The residue was purified bychromatography (silica gel, PE:EA (1:1, v:v)) to afford the desiredcompound (280 mg) as a colorless oil.

Tert-Butyl 4-(2-((1s,3s)-3-(benzyloxy)cyclobutoxy)ethyl)piperazine-1-carboxylate wasconverted to the title compound, 5-((5-(4-(2-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethyl)piperazin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione,according to the scheme below using procedures described above forExemplary Compound 42 and Exemplary Compound 53.

Exemplary Compound 56: ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H), 8.89 (s,1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.87 (d, J=6.2Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J=7.7 Hz, 1H),7.42 (s, 1H), 7.29 (d, J=11.5 Hz, 1H), 7.17 (d, J=6.5 Hz, 1H), 6.82 (d,J=8.2 Hz, 1H), 5.34 (s, 2H), 5.00-4.87 (m, 1H), 4.07 (s, 2H), 3.75 (s,1H), 3.57 (s, 1H), 3.04-2.49 (m, 10H), 2.20 (m, 4H), 2.01 (s, 4H), 1.85(s, 3H), 1.75-1.55 (m, 3H), 1.52 (s, 2H).

Exemplary Compound 54 and Exemplary Compound 58 were prepared accordingto the schemes below and using procedures analogous to those describedabove.

Synthetic Scheme for Exemplary Compound 57

Step 1: Benzyl 4-(5H-pyrido[4,3-b]indol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of 7-bromo-5H-pyrido[4,3-b]indole (492 mg, 2 mmol), benzyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (755 mg, 2.2 mmol), Pd(aMphose)Cl₂ (146 mg, 0.2 mmol)and CsF (1.2 g, 8 mmol) in dioxane/H₂O (20 mL/2 mL) was stirred at 90°C. for 16 hours. After cooling to room temperature, the reaction wasquenched by the addition of water (30 mL). The mixture was extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith brine (20 mL×2), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with dichloromethane/methanol to afford 260 mg (0.68mmol, 34%) of the desired product.

Step 2: 7-(piperidin-4-yl)-5H-pyrido[4,3-b]indole

To a solution of benzyl4-(5H-pyrido[4,3-b]indol-7-yl)-3,6-dihydropyridine-1 (2H)-carboxylate(130 mg, 0.34 mmol) and one drop conc. HCl in CH₃OH (10 mL) was addedPd/C (13 mg, 10%) at room temperature. The resulting solution wasstirred at room temperature overnight under 1 atm of H₂. Then the solidwas filtered off and the filtrate was concentrated under vacuum toafford crude product (80 mg), which was used in the next reactionwithout further purification.

Step 3:5-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)piperidin-1-yl)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of 7-(piperidin-4-yl)-5H-pyrido[4,3-b]indole (80 mg, 0.32mmol) and14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecanal(175 mg, 0.36 mmol) [prepared as described for intermediate 101 above]in CH₃OH (10 mL) were added NaBH₃CN (40 mg, 0.64 mmol) and one drop ofCH₃COOH at room temperature. After stirring for 2 hours, the reactionwas quenched by the addition of water (20 mL). The resulting solutionwas extracted with DCM (20 mL×3). The combined organic layers werewashed with brine (20 mL×2), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by prep-TLC withDCM/CH₃OH (10:1) to afford the desired product (18 mg, 0.025 mmol, 8%).¹H NMR (400 MHz, CD₃OD): δ 9.30 (s, 1H), 8.42-8.60 (m, 2H), 8.19 (d,J=8.0 Hz, 1H), 7.60-7.65 (m, 2H), 7.52 (s, 1H), 7.31 (d, J=8.0 Hz, 1H),7.19 (s, 1H), 7.12-7.14 (m, 1H), 5.07-5.10 (m, 1H), 4.12 (t, J=4.0 Hz,2H), 3.66-3.86 (m, 18H), 3.37 (s, 2H), 3.15-3.20 (m, 3H), 2.71-2.76 (m,3H), 2.09-2.22 (m, 5H). (M+H)⁺ 728.3.

Synthetic Scheme for Exemplary Compound 60

5-(4-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: tert-butyl 4-(3-((1r,3r)-3-((4-nitrobenzoyl)oxy)cyclobutoxy)propyl)piperazine-1-carboxylate

To a solution of tert-butyl-4-(3-((1s,3s)-3-hydroxycyclobutoxy)propyl)piperazine-1-carboxylate (530 mg, 1.68mmol), triphenylphosphine (1.32 g, 5.06 mmol) and 4-nitrobenzoic acid(310 mg, 1.85 mmol) in THF (10 mL) was added DIAD (1.02 g, 5.06 mmol)dropwise at room temperature under N2. After stirring at roomtemperature for 3 hours, it was quenched with water (20 mL), and themixture was extracted with EtOAc (20 mL×2). The combined organic layerswere concentrated under vacuum. The residue was purified by silica gelcolumn with PE/EA from 2:1 to 1:1 as eluent to afford the desiredproduct (350 mg, 45%) as a semi-solid.

Tert-butyl 4-(3-((1r,3r)-3-((4-nitrobenzoyl)oxy)cyclobutoxy)propyl)piperazine-1-carboxylatewas converted to the title compound, 5-(4-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione,according to the following scheme and using procedures described abovefor Exemplary Compound 53.

Compound 60: ¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 9.76 (s, 1H),8.67 (d, J=6.0 Hz, 1H), 8.60 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 8.16 (d,J=8.4 Hz, 1H), 8.80-8.02 (m, 2H), 7.77 (t, J=8.4 Hz, 2H), 7.50 (s, 1H),7.37 (d, J=8.0 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 5.36 (m, 1H), 5.07-5.11(m, 1H), 4.24 (br, 3H), 3.62 (br, 9H), 3.55 (s, 3H), 3.17-.3.25 (m, 6H),2.86-2.93 (m, 1H), 2.38-2.62 (m, 4H), 1.97-2.04 (m, 1H). (M+H)⁺ 714.3.

Synthetic Scheme for Exemplary Compound 61

2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione

Step 1:7-(6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridin-3-yl)-5H-pyrido[4,3-b]indole

To a solution of3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol (prepared asdescribed for Compound 55; 100 mg, 0.33 mmol) in DCM (5 mL) were addedimidazole (44.8 mg, 0.66 mmol) and TBSCl (59.6 mg, 0.40 mmol). Theresulting solution was stirred at 40° C. for 3 hours. The solvent wasremoved under reduced pressure. The residue was diluted with EA (30 mL),the mixture was washed with brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by silica gel column chromatography (DCM/MeOH=20/1,0.2% Net₃) to afford the title product (100 mg. 73% yield).

Step 2:7-(6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indole

To a solution of7-(6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridin-3-yl)-5H-pyrido[4,3-b]indole(60 mg, 0.14 mmol) in DMF (5 mL) was added NaH (8.6 mg, 0.22 mmol) at 5°C. After stirring for 20 min, a solution of CF₃CH₂Otf (66.6 mg, 0.29mmol) in DMF (1 mL) was added dropwise. The mixture was stirred foranother 1 hour, and the reaction was diluted by EtOAc (40 mL), washedwith brine, dried over anhydrous sodium sulfate. The filtrate wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel (DCM/MeOH=40:1, 0.2% NH₃—H₂O) to afford thetitle product (55 mg, 92%).

Step 3:3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol

To a solution of7-(6-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridin-3-yl)-5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indole(110 mg, 0.22 mmol) in CH₃OH (2 mL) was added HCl/Dioxane (6 N, 3 mL).The resulting solution was stirred at 5° C. for 1 hour. Then it wasdiluted with EtOAc (40 mL), and the mixture was washed with sat. NaHCO₃(a.q.) and brine, and dried over anhydrous sodium sulfate. The organicphase was evaporated under reduced pressure to afford crude titleproduct (84.9 mg) which was used in the next reaction without furtherpurification.

Step 4:3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propanal

To a solution of3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propan-1-ol(90 mg, 0.23 mmol) in DMSO (2 mL) was added IBX (130.9 mg, 0.47 mL). Theresulting mixture was stirred at 40° C. for 2 hours. The mixture wasquenched by sat. Na₂S₂O₃ a.q. (5 mL) and sat. NaHCO₃a.q. (5 mL). Themixture was extracted with EtOAc (20 mL×5). The combined organic layerwas dried over anhydrous sodium sulfate, concentrated under vacuum toafford crude desired product (89.5 mg) which was used in the nextreaction without further purification.

Step 5: tert-butyl4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazine-1-carboxylate

To a solution of5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanal(150 mg, 0.42 mmol) [prepared according to the procedures describedabove] in MeOH (5 mL) were added tert-butyl piperazine-1-carboxylate(77.9 mg, 0.42 mmol) and NaBH₃CN (52.6 mg, 0.84 mmol). The resultingsolution was stirred at 40° C. for 2 hours. The solvent was evaporatedunder reduced pressure. The residue was diluted with EA (30 mL), and themixture was washed with brine. The organic phase was dried overanhydrous sodium sulfate, filtered. The filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/MeOH=60/1) to afford the desired product (200 mg, 90% yield).

Using BOC-deprotection and reductive amination procedures analogous tothose described above, compounds of the steps 4 and 5 were convertedinto the final compound,2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione.

¹H NMR (400 MHz, CD₃OD) δ 9.35 (s, 1H), 8.89 (s, 1H), 8.55 (d, J=5.8 Hz,1H), 8.40 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 1H), 8.05 (s, 1H), 7.81 (d,J=8.3 Hz, 1H), 7.74 (d, J=5.6 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.40 (s,1H), 7.33 (s, 1H), 5.40 (d, J=9.1 Hz, 2H), 5.08-5.16 (m, 1H), 4.95 (s,4H), 4.59 (s, 2H), 4.18 (t, J=6.2 Hz, 1H), 2.91-3.00 (m, 2H), 2.58-2.91(m, 9H), 2.12-2.18 (m, 1H), 2.06 (s, 2H), 1.89 (s, 2H), 1.69 (s, 2H),1.57 (s, 2H). (M+H)⁺ 796.3.

Synthetic Scheme for Exemplary Compound 62

3-(5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Step 1: tert-butyl5-amino-4-(5-((5-hydroxypentyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

To a solution of tert-butyl5-amino-4-(5-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (500.0 mg,1.0 eq), pentane-1,5-diol (187 mg, 1.2 eq) and PPh3 (590.0 mg, 1.5 eq)in anhydrous tetrahydrofuran (50 mL) was added DIAD (455 mg, 2.25 mmol,1.5 eq). The resulting solution was stirred at room temperature for 16hours. Then the reaction was quenched by the addition of water (100 mL).The resulting solution was extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with brine (20 mL×2), dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with dichloromethane/methanol (10:1) toafford the desired product (560 mg. 1.33 mmol, 89%).

Step 2:3-(5-((5-hydroxypentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of tert-butyl5-amino-4-(5-((5-hydroxypentyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(560 mg, 1.0 eq) in MeCN (20 mL) was added p-TsA (253 mg, 3.0 eq) atroom temperature. The resulting solution was stirred at 90° C. for 6hours. Then the reaction was cooled to room temperature and quenched bythe addition of water (10 mL). The resulting solution was extracted withethyl acetate (15 mL×3). The combined organic layers were washed withbrine (10 mL×2), dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1) to afford the desired product (190 mg,0.55 mmol, 46%).

Step 3:5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pentanal

To a solution of3-(5-((5-hydroxypentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(190 mg, 1.0 equiv) in DCM (20 mL) was added IBX (100 mg, 2 eq) at roomtemperature. The resulting solution was stirred at room temperature for2 hours. Then the solid was filtered off and the filtrate wasconcentrated under vacuum to afford crude product (190 mg) which wasused into next reaction without further purification.

Step 4: 7-bromo-5-methyl-5H-pyrido[4,3-b]indole]

To a solution of 7-bromo-5H-pyrido[4,3-b]indole (8.0 g, 32.4 mmol) inN,N-dimethylformamide (50 ml) was added sodium hydride (1.4 g, 35.6mmol, 60% in mineral oil) at 0° C., and the reaction mixture was stirredat 0° C. for 30 minutes. To the resulting mixture was added iodomethane(4.6 g, 32.4 mmol) at 0° C., and the reaction mixture was allowed towarm up to room temperature and stirred overnight. TLC showed thereaction was complete. The reaction mixture was quenched with water (30ml) at 0° C., and extracted with ethyl acetate (50 ml×2). The combinedorganic layers were washed with water (80 ml) then brine (90 ml), driedover anhydrous sodium sulfate, and concentrated under reduced pressureto give a crude residue which was purified by silica gel flashchromatography (eluted with 20-40% ethyl acetate in hexane) to afford7-bromo-5-methyl-5H-pyrido[4,3-b]indole (6.0 g, yield 71%) as brownsolid.

Using procedures described above for the Exemplary Compound 61,5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pentanal wasconverted into the title compound,3-(5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneaccording to the scheme below.

Exemplary Compound 62: ¹HNMR (400 MHz, MeOD): δ 9.27 (s, 1H), 8.86 (d,J=2.0 Hz, 1H), 8.46 (d, J=6.0 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.16 (d,J=2.4 Hz, 1H), 7.90 (s, 1H), 7.59-7.70 (m, 3H), 7.47 (d, J=6.0 Hz, 1H),7.03-7.09 (m, 2H), 5.06-5.12 (m, 1H), 4.42 (d, J=5.6 Hz, 2H), 4.07 (t,J=6.4 Hz, 2H), 3.99 (s, 3H), 2.89-2.96 (m, 3H), 2.51-2.75 (m, 13H),2.12-2.24 (m, 1H), 2.01-2.03 (m, 3H), 1.82-1.84 (m, 2H), 1.52-1.63 (m,6H). (M+H)⁺ 714.3.

Exemplary Compound 63

2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dione

Step 1:5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole

To a solution of 7-bromo-5-methyl-5H-pyrido[4,3-b]indole (150 mg, 0.577mmol) in dioxane were added KOAc (114 mg, 1.15 mmol), Pd(dppf)Cl₂ (35mg, 0.05 mmol), and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (294 mg,1.15 mmol) subsequently. The resulting solution was heated to 100° C.overnight under N2. After cooling to room temperature, the reaction wasquenched with water, the mixture was extracted with EtOAc (10 mL×2). Thecombined organic layers were washed with brine (10 mL). The organicphase was dried over Na₂SO₄, concentrated under vacuum to afford crudedesired product (180 mg, crude), which was used into next reactionwithout further purification.

Step 2:7-(6-chloro-5-(trifluoromethyl)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole

To a mixture of 5-bromo-2-chloro-3-trifluoromethylpyridine (135 mg, 0.7mmol) and5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole(180 mg, 0.58 mmol) in dioxane/H₂O (v/v=10/1, 10 mL) were addedPd(dppf)₂Cl₂ (20 mg, 10%) and CsF (180 mg, 1.16 mmol). The mixture wasstirred at 80° C. overnight. The solution was quenched with water. Themixture was extracted with ethyl acetate (20 mL), and the combinedorganic layers were washed with brine (10 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by silica gel column chromatography toafford the desired product (170 mg, 95% yield).

Step 3: tert-butyl4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)piperazine-1-carboxylate

To a mixture of7-(6-chloro-5-(trifluoromethyl)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole(170 mg, 0.58 mmol) and tert-butyl4-(prop-2-ynyl)piperazine-1-carboxylate (156 mg, 0.69 mmol) in DMF (10mL) were added Pd(PPh₃)₂Cl₂ (17 mg, 10%), Cs₂CO₃ (378 mg, 1.16 mmol),DBU (30 mg, 0.116 mmol) and t-Bu₃P (25 mg, 0.116 mmol). The mixture wasmicrowave-heated at 150° C. for 10 minutes. The reaction mixture wasquenched with water. The mixture was extracted with ethyl acetate (20mL). The combined organic layers were washed with brine (10 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by silica gel columnchromatography to afford the desired product (200 mg).

Step 4: tert-butyl4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazine-1-carboxylate

To a solution of tert-butyl4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)prop-2-yn-1-yl)piperazine-1-carboxylate(200 mg) in ethanol was added Pd/C (20 mg). The mixture was stirred at30° C. under H₂ atmosphere (3 Mpa) for 8 hours. The mixture was filteredthrough Celite, and the filtrate was concentrated under vacuum. Theresidue was purified by prep-HPLC to afford the desired product (25 mg).

Using BOC-deprotection and reductive amination procedures describedabove tert-butyl4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazine-1-carboxylatewas converted into the title compound,2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)propyl)piperazin-1-yl)pentyl)oxy)isoindoline-1,3-dioneaccording to the scheme below.

Exemplary Compound 63: ¹H NMR (400 MHz, CD₃OD): δ 9.25 (s, 1H), 8.45 (s,1H), 8.23 (d, J=7.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.59(d, J=8.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.35 (s, 2H), 7.26-7.28 (m,1H), 6.06 (s, 1H), 5.72 (s, 1H), 5.06-5.08 (m, 1H), 4.30 (d, J=6.4 Hz,1H), 4.11-4.15 (m, 2H), 3.90-3.94 (m, 4H), 3.70-3.74 (m, 2H), 3.03-3.06(m, 2H), 2.82-2.88 (m, 4H), 2.71-2.75 (m, 6H), 2.51-2.55 (m, 3H),2.05-2.25 (m, 2H), 1.82-1.86 (m, 2H), 1.61-1.63 (m, 2H), 1.51-1.52 (m,2H). (M+H)⁺ 796.2.

Exemplary Compound 73

Step 1: 7-(6-((1s,3s)-3-(benzyloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

To a solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (1.1 g,4.18 mmol) and (1s, 3s)-3-(benzyloxy)cyclobutanol (745 mg, 4.18 mmol) in1-methylpyrrolidin-2-one (2 ml) was added sodium hydride (60% in mineraloil) (334 mg, 8.35 mmol) at 0° C. The mixture was stirred at roomtemperature for 2 hours. TLC showed the reaction was complete. Themixture was partitioned between ethyl acetate (20 ml) and water (20 ml).The organic layer was collected, washed with brine (30 ml), dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive a crude residue which was purified by silica gel flashchromatography (eluted with 2-5% methanol in dichloromethane) to afford7-(6-((1s,3s)-3-(benzyloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (1.42g, 82%) as white solid.

Step 2: (1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutan-1-ol

A mixture of 7-(6-((1s,3s)-3-(benzyloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole (1.42g, 3.37 mmol) and palladium on carbon (10%, 150 mg) in methanol (30ml)-tetrahydrofuran (10 ml) was stirred at 50° C. for 2 hours underhydrogen atmosphere (hydrogen balloon). TLC showed the reaction wascomplete. Palladium on carbon was removed through filtration and washedwith methanol (10 ml×2). The combined filtrate was concentrated underreduced pressure to afford (1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanol(1.57 g, crude) as white solid.

Step 3: tert-butyl 7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

To a suspension of (1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanol(1.57 g, 4.27 mmol) and sodium carbonate (1.1 g, 10.69 mmol) intetrahydrofuran (20 ml)-water (5 ml) was added di-tert-butyl carbonate(1.2 g, 5.55 mmol) at room temperature. The mixture was stirred at roomtemperature for 17 hours. TLC showed the reaction was complete. Themixture was concentrated and the residue was partitioned between ethylacetate (20 ml) and water (30 ml). The organic layer was collected,washed with brine (20 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a crude residue which waspurified by silica gel flash chromatography (eluted with 1-2% methanolin dichloromethane) to afford tert-butyl 7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate(1.1 g, two steps 73%) as white solid.

Step 4: tert-butyl 7-(6-((1s,3s)-3-((methylsulfonyl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

To a suspension of tert-butyl 7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate(500 mg, 1.16 mmol) and triethylamine (352 mg, 3.47 mmol) indichloromethane (10 ml) was added methanesulfonyl chloride (530 mg, 4.63mmol) at 0° C. The resulting mixture was allowed to warm up to roomtemperature and stirred at room temperature for 5 hours. TLC showed thereaction was completed. The mixture was diluted with dichloromethane (10ml) and washed with water (10 ml). The organic layer was washed withbrine (20 ml), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to afford tert-butyl 7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate(700 mg, crude) which was used in next step without furtherpurification.

Step 5: 7-(6-((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

A mixture of tert-butyl 7-(6-((1s,3s)-3-hydroxycyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate(350 mg, 0.69 mmol), 6-iodopyridin-3-ol (155 mg, 0.69 mmol) and cesiumcarbonate (452 mg, 1.39 mmol) in dry N,N-dimethylformamide (4 ml) wasstirred at 90° C. for 12 hours. TLC showed the reaction was complete.The mixture was partitioned between ethyl acetate (30 ml) and water (40ml). The organic layer was collected, washed with brine (30 ml), driedover anhydrous sodium sulfate, and concentrated under reduced pressureto give a crude residue which was purified by silica gel flashchromatography (eluted with 1-2% methanol in dichloromethane) to afford7-(6-((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(250 mg, 68%) as light yellow solid.

Step 6: [5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione]

To a stirred solution of 7-(6-((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(150 mg, 0.24 mmol),2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-yloxy)isoindoline-1,3-dione(111 mg, 0.35 mmol) [prepared using procedure of step 1 from ExemplaryCompound 180] and triethylamine (121 mg, 1.20 mmol) inN,N-dimethylformamide (2 ml) were addedBis(triphenylphosphine)palladium(II) chloride (8 mg, 0.01 mmol) andcuprous iodide (2 mg, 0.01 mmol) at room temperature under nitrogenatmosphere; the mixture was degassed with nitrogen three times. Theresulting mixture was stirred at 65° C. under nitrogen overnight. TLCshowed the reaction was complete. The mixture was partitioned betweenwater (30 ml) and ethyl acetate (30 ml). The organic layer was collectedand washed with brine (30 ml×2), dried over anhydrous sodium sulfate,and concentrated under reduced pressure to give a crude residue whichwas purified by silica gel flash column chromatography (eluted with 2%methanol in dichloromethane) to afford 5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(45 mg, yield 26%) as white solid.

¹H NMR (400 MHz, DMSOd-6): δ 2.04-2.07 (m, 1H), 2.57-2.77 (m, 6H),2.86-2.93 (m, 1H), 5.10-5.14 (m, 2H), 5.32 (s, 2H), 5.39-5.48 (m, 1H),6.97 (d, J=8.0 Hz, 1H), 7.32-7.33 (m, 1H), 7.46-7.58 (m, 5H), 7.77 (s,1H), 7.90 (d, J=7.2 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 8.25 (s, 1H), 8.30(d, J=7.6 Hz, 1H), 8.43 (s, 1H), 8.56 (s, 1H), 9.36 (s, 1H), 11.12 (s,1H), 11.82 (s, 1H). (M+H)⁺ 719.4.

Synthetic Scheme for Exemplary Compound 77

Step 1: tert-butyl 7-(6-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate

To a solution of tert-butyl 7-(6-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate(15 mg) in MeOH was added Pd/C. The solution was stirred at 30° C. for 2hours under H₂ (2 Mpa). The mixture was filtered through Celite, and thefiltrate was concentrated under vacuum. The residue was purified bysilica gel to afford the desired product (6 mg).

Step 2: 5-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A solution of tert-butyl 7-(6-((1r,3r)-3-((6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)238pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate(6 mg) in DCM/TFA (2 mL/1 mL) was stirred at room temperature for 4hours. The solvent was removed under vacuum to afford 5-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(5.5 mg).

¹H NMR (400 MHz, CD₃OD): δ 9.56 (s, 1H), 8.54-8.56 (m, 2H), 8.45 (d,J=8.4 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.97 (d,J=8.0 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.79 (s,1H), 7.76-7.78 (d, J=8 Hz, 1H), 7.29 (s, 1H), 7.21 (d, J=8.0 Hz, 1H),6.98 (d, J=8.0 Hz, 1H), 5.48-5.52 (m, 1H), 5.32-5.34 (m, 1H), 5.18-5.22(m, 1H), 5.06-5.10 (m, 1H), 4.25-4.28 (m, 2H), 3.21-3.23 (m, 3H),2.78-2.81 (m, 5H), 2.67-2.70 (m, 2H), 2.30-2.33 (m, 2H), 2.17-2.19 (m,1H), 1.97-2.07 (m, 3H). (M+H)⁺ 723.5.

Synthetic Scheme for Exemplary Compound 94

Step 1: (1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutan-1-ol

To a solution of (1r, 3r)-3-((6-bromopyridin-3-yl)oxy)cyclobutan-1-ol(530 mg, 2.17 mmol) in dry THF (10 mL) was addedtriisopropyl(pent-4-yn-1-yloxy)silane (626 mg, 2.61 mmol), TEA (1.1 g,10.86 mmol), CuI (45 mg, 0.24 mmol) and Pd(PPh₃)₂Cl₂ (110 mg, 4.34 mmol)at 25° C. under N2. The resulting solution was stirred at 45° C. for 16hours. The reaction was diluted with H₂O (10 mL). The resulting mixturewas extracted with EtOAc (10 mL×2). The combined organic layers weredried over anhydrous sodium sulfate and concentrated. The residue waspurified with silica gel column to afford the desired product (1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutan-1-ol(600 mg, 68% yield) as a colorless oil.

Step 2: 5-bromo-2-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridine

To a solution of (1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutan-1-ol (300 mg, 0.74 mmol) in DMF (5 mL) was added NaH (45mg, 1.11 mmol) at 0° C. The reaction was stirred at 0° C. for 0.5 hours,and 5-bromo-2-fluoropyridine (144 mg, 0.82 mmol) was added dropwise at0° C. The reaction was stirred at 20° C. for 2 hours. The reaction wasdiluted with a solution of H₂O (10 mL). The resulting mixture wasextracted with EtOAc (10 mL×2), the combined organic layers were driedover anhydrous sodium sulfate and concentration. The residue waspurified with silica gel column to afford the desired product5-bromo-2-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridine(240 mg, 58% yield) as a white solid.

Step 3: 5-methyl-7-(6-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

To a solution of 5-bromo-2-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridine (180 mg, 0.32 mmol) in 1,4-dioxane(5 ml) and H₂O (1 mL) was added5-methyl-7-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-5H-pyrido[4,3-b]indole(119 mg, 0.39 mmol), CsF (147 mg, 0.96 mmol) and Pd(aMphos)Cl₂ (34 mg,0.06 mmol) at 15° C. under N2. The resulting mixture was stirred at 80°C. for 5 hours. The mixture was quenched with H₂O (20 mL), extractedwith EtOAc (10 mL×2). Then the combined organic layers were washed withbrine (20 mL×2), dried over anhydrous sodium sulfate and concentrated.The residue was purified with silica gel column to afford the desiredproduct 5-methyl-7-(6-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(80 mg, 38% yield).

Step 4: 5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-ol

To a solution of 5-methyl-7-(6-((1r,3r)-3-((6-(5-((triisopropylsilyl)oxy)pent-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(90 mg, 0.14 mmol) in dry THF (10 mL) was added 1 M TBAF in THF (1 mL,0.7 mmol) under N2 at 15° C. The mixture was stirred at 40° C. for 1hour under N2 balloon. The mixture was concentrated. The residue waspurified with prep-TLC to afford the desired product 5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-ol(30 mg, 43% yield) as a white solid.

Step 5: 2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione

To a solution of 5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-ol(25 mg, 0.05 mmol) in dry THF (2 mL) was added2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (20 mg, 0.07mmol), PPh₃ (40 mg, 0.14 mmol) at 15° C. under N2. DIAD (32 mg, 0.14mmol) was added to the mixture at 40° C. under N2. The resulting mixturewas stirred at 40° C. for 0.5 hours. Cooled the mixture to 20° C. andquenched with H₂O (10 mL), extracted with EtOAc (10 mL×2). Then thecombined organic layers were washed with brine (20 mL×5), dried overanhydrous sodium sulfate and concentrated. The residue was purified withprep-TLC to afford the desired product2-(2,6-dioxopiperidin-3-yl)-5-((5-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)pent-4-yn-1-yl)oxy)isoindoline-1,3-dione(22 mg, 58% yield) as a white solid.

¹HNMR (400 MHz, DMSO-d₆): δ: 11.04 (s, 1H), 9.29 (s, 1H), 8.58 (d, J=2.0Hz, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.12-8.16 (m,2H), 7.92 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.56 (d, J=6.0 Hz, 2H), 7.40(s, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.20-7.22 (m, 1H), 6.92 (d, J=4.4 Hz,1H), 5.37 (s, 1H), 5.01-5.37 (m, 2H), 4.25 (t, J=6.0 Hz, 2H), 3.89 (s,3H), 2.43-2.65 (m, 9H), 1.98 (t, J=6.4 Hz, 3H). (M+H)⁺ 761.5.

Synthetic Scheme for Exemplary Compound 117

Step 1: 5-methyl-7-(6-((1r,3r)-3-((6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

A mixture of (1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutylmethanesulfonate (480 mg, 1.1 mmol) [prepared using procedure describedin step 4 of Exemplary Compound 73],6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-ol (256 mg,1.1 mmol) and cesium carbonate (715 mg, 2.2 mmol) inN,N-dimethylformamide (15 ml) was stirred at 70° C. for 16 hours. TLCshowed the reaction was complete. The reaction mixture was partitionedbetween water (20 ml) and ethyl acetate (40 ml). The organic layer wascollected, washed with brine (50 ml), dried over sodium sulfate andevaporated under reduced pressure to give a crude residue which waspurified by silica gel flash column chromatography (eluted with 0-30%ethyl acetate in hexane) to afford 5-methyl-7-(6-((1r,3r)-3-((6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(350 mg, yield 57%) as white solid.

Step 2: 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-ol

To the solution of 5-methyl-7-(6-((1r,3r)-3-((6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(350 mg, 0.62 mmol) in tetrahydrofuran (10 ml) was added aqueoushydrogen chloride (5 ml, 2M), and the reaction mixture was stirred atroom temperature for 1 hours. TLC showed the reaction was complete. Thereaction mixture was quenched with aqueous sodium bicarbonate solution(20 ml), and the reaction mixture was extracted with ethyl acetate (20ml). The organic layer was collected, and the aqueous layer wasextracted with ethyl acetate (10 ml×2). The combined organic layers werewashed with brine (10 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-ol(270 mg, crude) as white solid which was used in the next step withoutpurification.

Step 3: 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl4-methylbenzenesulfonate

A mixture of 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-ol(200 mg, crude), triethylamine (127 mg, 1.26 mmol) and4-methyl-benzenesulfonyl chloride (120 mg, 0.63 mmol) in dichloromethane(10 ml) was stirred at room temperature for 1 hour. The reaction mixturewas quenched with water (20 ml), extracted with dichloromethane (30 ml).The organic layer was washed with brine (20 ml), dried over sodiumsulfate and evaporated under reduced pressure to give a crude residuewhich was purified by silica gel flash column chromatography (elutedwith 5% methanol in dichloromethane) to afford 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl4-methylbenzenesulfonate (130 mg, yield 49%) as white solid.

Step 4: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione

To a solution of 3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl4-methylbenzenesulfonate (130 mg, 0.21 mmol), potassium carbonate (85mg, 0.62 mmol) and2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (57 mg, 0.21mmol) in N,N-dimethylformamide (10 ml) was added potassium iodide (35mg, 0.21 mmol) under nitrogen atmosphere. The resulting mixture waswarmed to 50° C. and stirred for 16 hours. TLC showed the reaction wascomplete. The reaction mixture was partitioned between water (20 ml) andethyl acetate (20 ml). The organic layer was collected, washed withbrine (10 ml), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give the crude product which was purified bysilica gel flash column chromatography (eluted with 8% methanol indichloromethane) to afford 2-(2,6-dioxopiperidin-3-yl)-5-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione(21.3 mg, yield 14%) as yellow solid.

¹H NMR (400 MHz, CD₃OD): δ 1.92-1.94 (m, 1H), 2.02-2.10 (m, 2H),2.62-2.65 (m, 5H), 3.90 (s, 3H), 4.97-5.02 (m, 2H), 5.10 (s, 2H), 5.37(t, J=6 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 7.20-7.22 (m, 1H), 7.34-7.41(m, 2H), 7.45 (d, J=2.0 Hz, 1H), 7.50-7.56 (m, 2H), 7.75-7.77 (m, 2H),8.02-8.06 (m, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.37 (d, J=6.0 Hz, 1H), 8.42(d, J=2.4 Hz, 1H), 9.18 (s, 1H). (M+H)⁺ 733.4.

Using procedures analogous to those described above for Compound 83(method of Compound 94), Compound 95, Compound 97 (method of Compound94), Compound 98, Compound 183 (method of Compound 73), Compound 204(combination of methods of Compound 73 and Compound 176) were prepared.

Synthetic Scheme for Exemplary Compound 102 and Exemplary Compound 110

2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione(Exemplary Compound 102) and 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hexyl)oxy)isoindoline-1,3-dione(Exemplary Compound 110)

Step 1: 7-(6-((1r,3r)-3-((5-iodopyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole

To a solution of (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanol(100 mg, 0.29 mmol) [prepared by using procedures analogous to the onesdescribed for steps 1 and 2 for Compound 73] in 1-methylpyrrolidin-2-one(5 ml) was added sodium hydride (60% in mineral oil) (58 mg, 1.45 mmol)at 0° C., and the reaction mixture was stirred for 1 hour. Then to thereaction mixture 2-fluoro-5-iodopyridine (65 mg, 0.29 mmol) was added,and the mixture was stirred at room temperature for 2 hours. TLC showedthe reaction complete. The reaction was quenched with water (10 ml) at0° C., extracted with ethyl acetate (20 ml×2). The combined organiclayers were washed with water (20 ml×2), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give a crude residuewhich was purified by silica gel flash chromatography (eluted with 5%methanol in dichloromethane) to afford 7-(6-((1r,3r)-3-((5-iodopyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole(100 mg, yield 63%) as a white solid.

Using procedures described for Compound 73, 7-(6-((1r,3r)-3-((5-iodopyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indolewas converted to the title compounds,2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione(Compound 102) and 2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-3-yl)hexyl)oxy)isoindoline-1,3-dione(Compound 110) according to the scheme below.

Compound 102: ¹HNMR (400 MHz, DMSO-d₆): δ 1.73 (d, J=7.2 Hz, 2H), 1.91(d, J=7.2 Hz, 2H), 2.01-2.08 (m, 1H), 2.51-2.67 (m, 8H), 2.83-2.94 (m,1H), 3.96 (s, 3H), 4.24 (t, J=6.0 Hz, 2H), 5.12 (dd, J=12.8, 5.2 Hz,1H), 5.31-5.52 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H),7.36 (d, J=8.2 Hz, 1H), 7.44 (s, 1H), 7.75-7.58 (m, 3H), 7.82 (d, J=8.2Hz, 1H), 7.99 (s, 1H), 8.10-8.28 (m, 2H), 8.33 (d, J=8.2 Hz, 1H), 8.52(s, 1H), 8.64 (d, J=1.6 Hz, 1H), 9.40 (s, 1H), 11.11 (s, 1H). (M+H)⁺775.5

Compound 110: ¹H NMR (400 MHz, DMSO-d₆): δ 1.36 (d, J=7.6 Hz, 2H), 1.45(d, J=6.8 Hz, 2H), 1.52-1.61 (m, 2H), 1.70-1.80 (m, 2H), 1.98-2.02 (m,3H), 2.54-2.70 (m, 6H), 2.89 (t, J=16.6 Hz, 1H), 3.96 (s, 3H), 4.16 (d,J=5.0 Hz, 2H), 5.12 (dd, J=12.8, 4.4 Hz, 1H), 5.36-5.43 (m, 2H), 6.77(d, J=8.4 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.42(s, 1H), 7.60-7.64 (m, 3H), 7.83 (d, J=8.0 Hz, 1H), 7.97 (dd, J=14.0,6.4 Hz, 2H), 8.33 (d, J=8.4 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.50 (d,J=4.8 Hz, 1H), 8.65 (s, 1H), 9.37 (s, 1H), 11.11 (s, 1H). (M+H)⁺ 779.5

Synthetic Scheme for Exemplary Compound 173

5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: 2-(prop-2-yn-1-yloxy)ethan-1-ol

To a stirred mixture of sodium hydride (60% in mineral oil, 115 mg, 2.8mmol) in anhydrous N,N-dimethylformamide (20 ml) at 0° C. was addedethane-1,2-diol (3.9 g, 63 mmol) and stirred at 0° C. for 0.5 hour. Tothe resulting mixture was added 3-bromoprop-1-yne (5.0 g, 42 mmol) at 0°C. and stirred at 50° C. overnight. TLC showed the reaction wascomplete. The reaction mixture was quenched with ice water (20 ml) andpartitioned between ethyl acetate (80 ml) and water (100 ml). Theorganic layer was collected, and the aqueous layer was extracted withethyl acetate (50 ml×2). The combined organic layers were washed withbrine (80 ml), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a crude residue which was purified bysilica gel flash chromatography (eluted with 0-20% ethyl acetate inhexane) to afford 2-(prop-2-yn-1-yloxy)ethanol (3.4 g, yield 80%) ascolorless oil.

Step 2: 2-(prop-2-yn-1-yloxy)ethyl 4-methylbenzenesulfonate

To a stirred solution of 2-(prop-2-yn-1-yloxy)ethanol (1 g, 10 mmol),triethylamine (3 g, 3 mmol) and N,N-dimethylpyridin-4-amine (20 mg, 1mmol), in dichloromethane (20 ml) was added p-toluenesulfonic acid 2.9g, 15 mmol) at 0° C. The reaction mixture was allowed to warm up to roomtemperature and stirred at room temperature overnight. The reactionmixture was diluted with dichloromethane (20 ml), washed with brine (50ml), dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford crude residue. It was purified by silica gel flashcolumn chromatography (eluent 10-20% ethyl acetate in hexane) to afford2-(prop-2-yn-1-yloxy)ethyl 4-methylbenzenesulfonate (700 mg, yield: 40%)as light yellow oil.

Step 3:2-(2,6-dioxopiperidin-3-yl)-5-(2-(prop-2-yn-1-yloxy)ethoxy)isoindoline-1,3-dione

To a stirred solution of 2-(prop-2-yn-1-yloxy)ethyl4-methylbenzenesulfonate (700 mg, 2.8 mmol) and potassium carbonate (1.1g, 8.3 mmol) in N,N-dimethylformamide (15 ml) was added2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (755 mg, 2.8mmol) at room temperature. The resulting mixture was stirred at 50° C.overnight. TLC showed the reaction was complete. The mixture solutionwas cooled to room temperature. The reaction mixture was partitionedbetween ethyl acetate (20 ml) and water (30 ml); the organic layer wascollected and the aqueous layer was extracted with ethyl acetate (20ml×2). The combined organic layers were washed with brine (30 ml), driedover anhydrous sodium sulfate, and concentrated under reduced pressureto give a crude residue which was purified by silica gel flashchromatography (eluted with 0-50% ethyl acetate in hexane) to afford2-(2,6-dioxopiperidin-3-yl)-5-(2-(prop-2-yn-1-yloxy)ethoxy)isoindoline-1,3-dione(290 mg, yield 30%) as light yellow solid.

2-(2,6-dioxopiperidin-3-yl)-5-(2-(prop-2-yn-1-yloxy)ethoxy)isoindoline-1,3-dionewas reacted with 7-(6-((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indoleusing procedure described for Compound 73 to produce the title compound,5-(2-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

¹H NMR (400 MHz, DMSO-d6): δ 2.02-2.08 (m, 1H), 2.52-2.76 (m, 6H),2.85-2.93 (m, 1H), 3.89-3.95 (m, 2H), 4.37-4.42 (m, 2H), 4.49 (s, 2H),5.06-5.14 (m, 2H), 5.40-5.47 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.30-7.33(m, 1H), 7.38-7.40 (m, 1H), 7.46-7.48 (m, 2H), 7.62-7.64 (m, 2H),7.82-7.84 (m, 2H), 8.14-8.17 (m, 1H), 8.24 (d, J=2.8 Hz, 1H), 8.36-8.38(m, 1H), 8.49 (d, J=6 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 9.47 (s, 1H),11.11 (s, 1H), 12.14-12.28 (m, 1H). (M+H)+763.5.

Using procedures analogous to those described above Compounds 110(method of Compound 102), 124, 144 (method of Compound 102), 145, 146,147 (method of Compound 94), 172 (method of Compound 73), 179 (method ofCompound 173), 188 (method of Compound 173), 189 (method of Compound 73)were prepared.

Synthetic Scheme for Exemplary Compound 180

Step 1: tert-butyl(S)-5-amino-5-oxo-4-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)pentanoate

To a stirred solution of (S)-tert-butyl5-amino-4-(5-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (450 mg, 1.35mmol), and 3-bromoprop-1-yne (192 mg, 1.62 mmol) inN,N-dimethylformamide (4 ml) was added potassium carbonate (372 mg, 2.69mmol) and potassium iodide (22.4 mg, 0.135 mmol), and the mixture wasstirred at 50° C. overnight under nitrogen. LCMS showed formation ofdesired product. The mixture was partitioned between ethyl acetate (50ml) and water (30 ml). The organic layer was washed with brine (30 ml),dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give a crude residue which was purified by silica gel flashchromatography (eluted with 50% ethyl acetate in hexane and added 5%methanol) to afford (S)-tert-butyl5-amino-5-oxo-4-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)pentanoate(489 mg, yield 97%) as colorless oil.

Step 2:3-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)piperidine-2,6-dione

To a stirred solution of (S)-tert-butyl5-amino-5-oxo-4-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)pentanoate(325 mg, 0.873 mmol) in anhydrous tetrahydrofuran (20 ml) was addeddropwise potassium tert-butoxide (1N, in THF) (107.7 mg, 0.96 mmol) at0° C. under nitrogen atmosphere. The reaction mixture was stirred at thesame temperature for 20 minutes. LCMS showed formation of desiredproduct. The reaction mixture was quenched with water (20 ml), andextracted with ethyl acetate (50 ml). The organic layer was collected,washed with water (20 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a crude residue which waspurified by silica gel flash chromatography (eluted with 50% ethylacetate in hexane and added 10% methanol) to afford3-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)piperidine-2,6-dione (128mg, yield 49%) as white solid.

Step 3: 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a stirred solution of3-(1-oxo-5-(prop-2-yn-1-yloxy)isoindolin-2-yl)piperidine-2,6-dione (50mg, 0.168 mmol), 7-(6-((1r,3r)-3-((6-iodopyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(74 mg, 0.14 mmol) and triethylamine (70.7 mg, 0.70 mmol) inN,N-dimethylformamide (1 ml) were addedtrans-dichlorobis(triphenylphosphine) palladium(II) (4.91 mg, 0.007mmol) and copper iodide (1.33 mg, 0.007 mmol) at room temperature undernitrogen atmosphere; the mixture was degassed with nitrogen three times.The resulting mixture was stirred at 65° C. for 12 hours. TLC showed thereaction was complete. TLC showed the reaction was complete. The mixturewas partitioned between ethyl acetate (50 ml) and water (30 ml). Theorganic layer was washed with brine (30 ml), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give a crude residuewhich was purified by prep TLC (eluted with 10% methanol indichloroethane) to afford 3-(5-((3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(19 mg, 16%) as white solid.

¹HNMR (400 MHz, DMSO-d6): δ 1.97-2.00 (m, 1H), 2.33-2.44 (m, 2H),2.55-2.67 (m, 4H), 2.86-2.96 (m, 1H), 4.29 (d, J=17.2 Hz, 1H), 4.42 (d,J=16.8 Hz, 1H), 5.06-5.10 (m, 2H), 5.18 (s, 2H), 5.42-5.45 (m, 1H), 6.99(d, J=8.4 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.29-7.33 (m, 2H), 7.50 (d,J=8.4 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.74 (d, J=5.6 Hz, 1H), 7.89 (s,1H), 8.16 (d, J=7.6 Hz, 1H), 8.24 (s, 1H), 8.41 (d, J=7.6 Hz, 1H),8.53-8.59 (m, 2H), 9.56 (s, 1H), 10.97 (s, 1H), 12.54 (br, 1H). (M+H)⁺705.4.

Synthetic Scheme for Exemplary Compound 64

5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

The title compound was prepared according to the scheme below usingprocedures described above for other targets and common procedures knownto those skilled in the art. The starting tert-butyl 7-(6-((1r,3r)-3-((6-(3-hydroxyprop-1-yn-1-yl)pyridin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylatewas prepared according to the procedures described for the Compound 117.

5-(4-(3-(5-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

¹H NMR (400 MHz, CD₃OD) δ 9.42 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.50 (d,J=6.1 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.13 (d, J=8.0 Hz, 2H), 7.87 (s,1H), 7.71-7.78 (m, 2H), 7.68 (d, J=8.3 Hz, 1H), 7.42 (s, 1H), 7.33 (s,2H), 7.29 (d, J=8.6 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 5.51 (s, 2H),5.06-5.14 (m, 2H), 3.55 (s, 4H), 2.58-3.03 (m, 15H), 2.04 (m, 3H).

Synthetic Scheme for Exemplary Compound 67

Step 1:14-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol

To a solution of pentaethylene glycol (330 mg, 1.38 mmol) in THF (5 mL)was added NaH (30 mg, 0.76 mmol) at 0° C. The solution was stirred atroom temperature for 1 hour. Then5-bromo-2-chloro-3-(trifluoromethyl)pyridine (180 mg, 0.69 mmol) wasadded. The resulting solution was stirred at 80° C. for 2 hours. Thereaction solution was quenched with water. The mixture was extractedwith ethyl acetate (20 mL). The combined organic layers were washed withbrine (10 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated to afford the desired compound (400mg, crude), which was used into the next step without furtherpurification.

Step 2:14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol

A mixture of14-((5-bromo-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol

(180 mg, 0.39 mmol),5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole(120 mg, 0.39 mmol) [prepared as described in step 1 of Compound 63],Pd(amphos)Cl₂ (20 mg, 10%) and CsF (118 mg, 0.78 mmol) in dioxane/H₂O(10/1, 5 mL) was stirred at 80° C. for 2 hours. The reaction mixture wasquenched with water. The mixture was extracted with ethyl acetate (20mL). The organic layer was dried over Na₂SO₄, filtered and concentratedunder vacuum. The residue was purified by silica gel columnchromatography to afford the desired compound (85 mg, 47% yield).

Step 3:2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

To a solution of14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol(85 mg, 0.15 mmol),2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (41 mg, 0.15mmol) and PPh₃ (47 mg, 0.18 mmol) in THF was added DIAD (45 mg, 0.22mmol) at 40° C. The mixture was stirred at 40° C. for 1 hour. Thereaction solution was quenched with water. The mixture was extractedwith ethyl acetate (20 mL). The combined organic layers were washed withbrine (10 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gel columnchromatography to afford the title compound (34 mg, 28% yield).

¹H NMR (400 MHz, CD₃OD): δ 9.25 (s, 1H), 8.79 (s, 1H), 8.37-8.39 (d,J=8.0 Hz, 1H), 8.28-8.30 (d, J=8.0 Hz, 2H), 7.89 (s, 1H), 7.63-7.65 (d,J=8.0 Hz, 1H), 7.54-7.56 (m, 2H), 7.26 (s, 1H), 7.18-7.20 (m, 1H),5.02-5.05 (m, 1H), 4.62-4.64 (m, 2H), 4.17-4.19 (m, 2H), 3.95 (s, 3H),3.88-3.90 (m, 2H), 3.82-3.84 (m, 2H), 3.61-3.71 (m, 13H), 2.55-2.81 (m,3H), 2.95-2.99 (m, 1H). (M+H)⁺ 820.5.

Using procedures of Compound 67 the following were prepared: Compound69, Compound 113.

Synthetic Scheme for Exemplary Compound 65

Step 1: 4-((1r, 3r)-3-(benzyloxy)cyclobutoxy)pyridine

To a solution of pyridin-4-ol (3.20 g, 33.66 mmol, 1.5 eq) and3-benzyloxycyclobutanol (4 g, 22.44 mmol, 1 eq) in tetrahydrofuran (200mL) was added triphenylphosphine (7.06 g, 26.93 mmol, 1.2 eq) anddiisopropyl azodicarboxylate (5.45 g, 26.93 mmol, 1.2 eq) in one portionat 10° C. under nitrogen. The mixture was stirred at 50° C. for 12hours. The reaction mixture was concentrated under reduced pressure toremove tetrahydrofuran. Water (50 mL) was poured into the mixture andstirred for 1 minute. The aqueous phase was extracted withdichloromethane (50 mL×3). The combined organic phase was washed withbrine (50 mL×2), dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by silica gel columnchromatography (petroleum ether: tetrahydrofuran from 20:1 to 5:1). HPLCshowed 41% of the product in 254 mm. The residue was purified by flashC18 column chromatography [acetonitrile: water (0.5% ammoniumhydroxide)=5%-50%]. Compound 4-(3-benzyloxycyclobutoxy) pyridine (3.2 g,12.53 mmol, 55% yield) was obtained as a white solid.

Step 2: 1-benzyl-4-((1r, 3r)-3-(benzyloxy)cyclobutoxy)pyridin-1-iumbromide

To a solution of 4-(3-benzyloxycyclobutoxy)pyridine (4.2 g, 16.45 mmol,1 eq) in toluene (65 mL) was added benzyl bromide (2.81 g, 16.45 mmol, 1eq). The mixture was stirred at 80° C. for 12 hours. The reactionmixture was concentrated under reduced pressure to remove toluene. Thecrude product was triturated with petroleum ether (80 mL). Compound1-benzyl-4-((1r, 3r)-3-(benzyloxy)cyclobutoxy)pyridin-1-ium bromide (6.5g, 15.25 mmol, 92% yield) was obtained as a white solid.

Step 3: 1-benzyl-4-((1r,3r)-3-(benzyloxy)cyclobutoxy)-1,2,3,6-tetrahydropyridine

To a solution of 1-benzyl-4-((1r,3r)-3-(benzyloxy)cyclobutoxy)pyridin-1-ium bromide (6.5 g, 15.25 mmol, 1eq) in ethanol (120 mL) was added sodium borohydride (3.46 g, 91.47mmol, 6 eq) at 0° C. The mixture was stirred at 15° C. for 4 hours. Thereaction mixture was concentrated under reduced pressure to removeethanol. The residue was diluted with water (25 mL) and extracted withethyl acetate (50 mL×2). The combined organic phase was washed withsaturated brine (40 mL×3), dried with anhydrous sodium sulfate, filteredand concentrated in vacuum. Compound1-benzyl-4-(3-benzyloxycyclobutoxy)-3,6-dihydro-2H-pyridine (4.5 g,12.88 mmol, 84% yield) was obtained as a colorless oil.

Step 4: (1r, 3r)-3-((1-benzylpiperidin-4-yl)oxy)cyclobutan-1-ol

To a solution of1-benzyl-4-(3-benzyloxycyclobutoxy)-3,6-dihydro-2H-pyridine (4.5 g,12.88 mmol, 1 eq) in tetrahydrofuran (95 mL) and ethanol (70 mL) wasadded palladium on activated carbon catalyst (0.5 g, 10% purity) undernitrogen atmosphere. The suspension was degassed and purged withhydrogen for 3 times. The mixture was stirred under hydrogen (50 Psi) at25° C. for 24 hours. LCMS showed the reaction was not completed. Themixture was then stirred at 35° C. for 12 hours. The reaction mixturewas filtered and the filtrate was concentrated. The residue was purifiedby silica gel column chromatography (dichloromethane:methanol:ammoniumhydroxide from 20:1:0 to 10:1:0.1). Compound3-[(1-benzyl-4-piperidyl)oxy]cyclobutanol (2.8 g, 10.71 mmol, 83% yield)was obtained as a colorless oil.

Step 5: tert-butyl 4-((1r,3r)-3-hydroxycyclobutoxy)piperidine-1-carboxylate

To a solution of 3-[(1-benzyl-4-piperidyl)oxy]cyclobutanol (1.1 g, 4.21mmol, 1 eq) in methanol (10 mL) was added palladium hydroxide (591 mg)and di-tert-butyl carbonate (1.84 g, 8.42 mmol, 2 eq) under nitrogenatmosphere. The suspension was degassed and purged with hydrogen for 3times. The mixture was stirred under hydrogen (50 Psi) at 25° C. for 12hours. The reaction mixture was filtered and the filter wasconcentrated. The residue was purified by silica gel chromatography(petroleum ether: ethyl acetate=20:1 to 2:1). Compound tert-butyl4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (820 mg, 3.02 mmol, 71%yield) was obtained as a colorless oil.

Step 6: tert-butyl 4-((1r,3r)-3-((5-bromopyridin-2-yl)oxy)cyclobutoxy)piperidine-1-carboxylate

To a mixture of tert-butyl4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (400 mg, 1.47 mmol, 1eq) and 5-bromo-2-fluoro-pyridine (285 mg, 1.62 mmol, 1.1 eq) indimethylformamide (8 mL) was added cesium carbonate (960 mg, 2.95 mmol,2 eq) in one portion at 25° C. under nitrogen atmosphere. The mixturewas stirred at 100° C. for 2 hours. The reaction mixture was poured intowater (30 mL) and stirred for 5 minutes. The aqueous phase was extractedwith ethyl acetate (20 mL×3). The combined organic phase was washed withbrine (30 mL×3), dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (1000 mesh silica gel, petroleum ether/ethyl acetate from200:1 to 20:1). The product, tert-butyl4-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy] piperidine-1-carboxylate (560mg, 1.30 mmol, 88% yield), was obtained as a colorless oil.

Step 7: tert-butyl 4-((1r,3r)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidine-1-carboxylate

To a suspension of tert-butyl4-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carboxylate (560mg, 1.31 mmol, 1 eq),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (432 mg,1.70 mmol, 1.3 eq) and potassium acetate (257 mg, 2.62 mmol, 2 eq) indioxane (20 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (95 mg, 0.13 mmol, 0.1 eq). The mixturewas degassed in vacuum and purged with nitrogen for 3 times. The mixturewas heated to 80° C. and stirred at 80° C. for 15 hours. The mixture wasfiltered, and the filtrate was concentrated in vacuum. The residue waspurified by silica gel column chromatography (petroleum ether/ethylacetate from 20:1 to 10:1). Tert-butyl4-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate(500 mg, 1.05 mmol, 80% yield) as a colorless oil was obtained.

Step 8: tert-butyl 4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidine-1-carboxylate

To a solution of tert-butyl4-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate (240 mg, 0.50 mmol, 1 eq),7-bromo-5H-pyrido [4,3-b]indole (125 mg, 0.50 mmol, 1 eq) and potassiumcarbonate (140 mg, 1.01 mmol, 2 eq) in a mixture of dimethylformamide (8mL) and water (2 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05mmol, 0.1 eq). The mixture was degassed in vacuum and purged withnitrogen three times. The mixture was stirred at 100° C. for 3 hours.The mixture was poured into 50 mL saturated brine, and then extractedwith ethyl acetate (50 mL×2). The combined organic layer was washed withbrine (50 mL×3), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by preparative thinlayer chromatography (dichloromethane:methanol=20:1). Tert-butyl4-[3-[[5-(5H-pyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate(175 mg, 0.34 mmol, 67% yield) as an off-white solid was obtained.

Step 9: 7-(6-((1r,3r)-3-(piperidin-4-yloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

Tert-butyl4-[3-[[5-(5H-pyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate(170 mg, 0.33 mmol, 1 eq) in hydrochloric acid (4 M in dioxane, 8 mL,100 eq) was stirred at 25° C. for 10 minutes. The mixture wasconcentrated in vacuum. The product7-[6-[3-(4-piperidyloxy)cyclobutoxy]-3-pyridyl]-5H-pyrido[4,3-b]indole(190 mg, crude, hydrochloride) was obtained as a brown solid and wasdirectly used in the next step without further purification.

Step 10:5-((5,5-dimethoxypentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (548 mg, 2.00mmol, 1 eq) and 5-bromo-1,1-dimethoxypentane (506 mg, 2.40 mmol, 1.2 eq)in a mixture of acetone (3 mL) and dimethylformamide (3 mL) was addedpotassium carbonate (552 mg, 4.00 mmol, 2 eq). The mixture was heated to50° C. and stirred at 50° C. for 2 hours. The mixture was poured into 50mL 0.1 M aqueous hydrochloric acid, and then extracted with ethylacetate (50 mL×2). The combined organic layer was washed with brine (50mL×3), dried over anhydrous sodium sulfate, filtered and concentrated invacuum. The residue was purified by preparative thin layerchromatography (dichloromethane:methanol=20:1).5-((5,5-dimethoxypentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(120 mg, 0.30 mmol, 14% yield) as a colorless oil was obtained.

Step 11:5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanal

To a mixture of5-(5,5-dimethoxypentoxy)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(120 mg, 0.29 mmol, 1 eq) in tetrahydrofuran (10 mL) was added sulfuricacid (2 M in water, 7 mL, 50 eq) in one portion at 25° C. under nitrogenatmosphere. The mixture was stirred at 70° C. for 1 hour. The aqueousphase was extracted with ethyl acetate (20 mL×3). The combined organicphase was washed with saturated aqueous sodium bicarbonate (20 mL×2),and then brine (20 mL×3), dried with anhydrous sodium sulfate, filteredand concentrated in vacuum. The product5-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxypentanal (93mg, crude) was obtained as a light yellow solid.

Step 12: 5-((5-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a mixture of7-[6-[3-(4-piperidyloxy)cyclobutoxy]-3-pyridyl]-5H-pyrido[4,3-b]indole(110 mg, 0.24 mmol, 1 eq, hydrochloride) in dichloroethane (2 mL) andmethanol (5 mL) was added sodium acetate (40 mg, 0.49 mmol, 2 eq) in oneportion at 20° C. The mixture was stirred at 20° C. for 10 minutes.5-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxypentanal (88mg, 0.24 mmol, 1 eq) was added. The mixture was stirred at 20° C. for 10minutes. And then acetic acid (0.02 mL) and sodium cyanoborohydride (31mg, 0.49 mmol, 2 eq) was added in one portion. The mixture was stirredat 35° C. for 40 minutes. The mixture was filtered and the filtrate wasconcentrated in vacuum. The residue was purified by Semi-preparativereverse phase HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobilephase: [water (0.225% formic acid)-acetonitrile]; B %: 3%-33%, 10 min).The product2-(2,6-dioxo-3-piperidyl)-5-[5-[4-[3-[[5-(5H-pyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]isoindoline-1,3-dione triformate (50.2mg, 0.05 mmol, 21% yield) was obtained as an off-white solid.

¹H NMR: (400 MHz, DMSO-d6) δ: 11.80 (s, 1H), 11.11 (s, 1H), 9.35 (s,1H), 8.55 (d, J=2.4 Hz, 1H), 8.42 (d, J=5.6 Hz, 1H), 8.29 (d, J=8.4 Hz,1H), 8.18 (s, 3H), 8.11 (dd, J=2.4, 8.8 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H),7.76 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.48 (d, J=5.6 Hz, 1H), 7.42 (d,J=2.0 Hz, 1H), 7.35 (dd, J=2.0, 8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H),5.30 (d, J=3.6 Hz, 1H), 5.11 (dd, J=5.6, 13.2 Hz, 1H), 4.35 (t, J=6.4Hz, 1H), 4.17 (t, J=6.4 Hz, 2H), 2.93-2.84 (m, 2H), 2.77 (s, 2H),2.63-2.54 (m, 3H), 2.37 (d, J=6.0 Hz, 4H), 2.22-1.98 (m, 4H), 1.87-1.74(m, 4H), 1.53-1.38 (m, 6H). (M+H)⁺ 757.5

Using procedures, analogous to those described above, the following wereprepared: Compounds 82, 123 (as described for Compounds 65 and 67 anddetailed in the scheme below).

Synthetic Scheme for Exemplary Compound 66

5-(4-(2-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: benzyl 4-(2,2-diethoxyethyl)piperazine-1-carboxylate

To a solution of benzyl piperazine-1-carboxylate (1.0, 4.54 mmol) in DMF(20 mL) was added K₂CO₃ (1.25 g, 9.0 mmol) and2-bromo-1,1-diethoxyethane (1.0 g, 4.54 mmol). The resulting mixture wasstirred at 80° C. for 20 hours. Then the reaction mixture was dilutedwith water (50 mL) and extracted with EA. The organic phase was washedwith brine, dried over MgSO₄, and concentrated. The residue was purifiedby chromatography (silica gel, PE:EA=1:1) to afford the desired compoundbenzyl 4-(2,2-diethoxyethyl)piperazine-1-carboxylate (1.55 g) as acolorless oil.

Step 2: 1-(2,2-diethoxyethyl)piperazine

To a solution of benzyl 4-(2,2-diethoxyethyl)piperazine-1-carboxylate(1.55 g, 4.6 mmol) in MeOH (30 mL) was added Pd(OH)₂/C (0.3 g, 20%). Theresulting mixture was stirred at 30° C. for 3 hours. Then the reactionmixture was filtered and concentrated to afford the desired compound1-(2,2-diethoxyethyl)piperazine (0.9 g, crude) as a white solid, whichwas used to next step without further purification.

Step 3:5-(4-(2,2-diethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of 1-(2,2-diethoxyethyl)piperazine (0.9 g, 4.45 mmol) inNMP (15 mL) was added DIEA (2.3 g, 17.8 mmol) and2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.35 g, 4.9mmol). The resulting mixture was stirred at 90° C. for 20 hours. Thenthe reaction mixture was diluted with water (50 mL) and extracted withDCM/MeOH (10/1). The organic phase was washed with brine, dried overMgSO₄, and concentrated. The residue was purified by chromatography(silica gel, DCM:MeOH (20:1) to afford the desired compound (1.4 g) as ayellow solid.

Step 4:2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde

A solution of5-(4-(2,2-diethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(300 mg, 0.65 mmol) in HCl (5 mL in H₂O, 2.5 mol/L) was stirred at 50°C. for 20 hours. The mixture was basified with NaHCO₃ (20 mL) andextracted with EA. The organic phase was washed with brine, dried overMgSO₄, and concentrated to afford the desired compound (220 mg, crude)as yellow solid, which was used in the next step without furtherpurification.

Step 5: 5-(4-(2-(4-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde(180 mg, 0.41 mmol) in MeOH/DMSO (8 mL, 1/1) was added 7-(6-((1r,3r)-3-(piperidin-4-yloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(97 mg, 0.24 mmol) [prepared as described in Compound 65], AcOH (1 drop)and NaBH₃CN (60 mg, 0.94 mmol). The resulting mixture was stirred at 10°C. for 2 hours. Then the reaction mixture was diluted with water (10 mL)and extracted with EA. The organic phase was washed with brine andfiltered, and the crude material was purified by prep-HPLC to give thetitle compound (21.2 mg) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 13.21 (s, 1H), 11.08 (s, 2H), 9.76 (s, 1H),8.67 (d, J=6.6 Hz, 1H), 8.61 (s, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.17 (d,J=8.3 Hz, 1H), 8.02 (d, J=7.1 Hz, 2H), 7.82-7.72 (m, 3H), 7.46 (s, 2H),7.35 (s, 2H), 6.96 (d, J=8.5 Hz, 1H), 5.34 (s, 1H), 5.08 (d, J=7.7 Hz,2H), 4.40 (s, 2H), 3.23 (s, 4H), 3.15 (s, 4H), 3.02 (s, 4H), 2.95-2.83(m, 4H), 2.59 (d, J=15.7 Hz, 4H), 2.44 (s, 2H), 2.01 (s, 5H), 1.77 (d,J=14.7 Hz, 2H). (M+H)⁺ 783.6.

Synthetic Scheme for Exemplary Compound 171

5-((4,4-difluoro-5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: O5-tert-butyl O1-ethyl 2,2-difluoropentanedioate

A mixture of tert-butyl prop-2-enoate (10 g, 78.02 mmol, 1.00 eq), ethyl2-bromo-2,2-difluoro-acetate (28.51 g, 140.44 mmol, 1.8 eq) and copper(10.41 g, 163.85 mmol, 2.10 eq) in tetrahydrofuran (100 mL) was heatedto 55° C. under intense stirring; thenN,N,N′,N′-tetramethylethylenediamine (4.53 g, 39.01 mmol, 0.50 eq)followed by acetate acid (4.22 g, 70.22 mmol, 0.90 eq) were added. Thedark blue-brown reaction mixture was stirred for 1 hour at 55° C. A 10%aqueous solution of ammonium chloride (100 mL) and ethyl acetate (500mL) was added. The resulting mixture was stirred for 0.5 hours at roomtemperature and filtered through celite. The organic phase was washedwith another portion of ammonium chloride solution (100 mL×5) to removeremaining copper complexes (blue color). The solution was dried withanhydrous sodium sulfate, filtered, and evaporated under vacuum. Theresidue was purified by silica gel chromatography (Petroleum ether/Ethylacetate=500/1, 100/1) to afford 05-tert-butyl 01-ethyl2,2-difluoropentanedioate (18.6 g, 73.74 mmol, 95% yield) as a yellowoil.

Step 2: tert-butyl 4,4-difluoro-5-hydroxy-pentanoate

A suspension of sodium borohydride (3.24 g, 85.63 mmol, 1.20 eq) inethanol (100 mL) was cooled to 0° C. in an ice bath, and a solution of05-tert-butyl 01-ethyl 2,2-difluoropentanedioate (18 g, 71.36 mmol, 1.00eq) in ethanol (100 mL) was added drop-wise from the addition funnelunder vigorous stirring. The rate of dropping was carefully controlledto keep the reaction mixture temperature between 0-15° C. Then themixture was stirred at 15° C. for 1 hour. The reaction mixture wasquenched by dropwise addition of 5% aqueous citric acid (40 mL) withcooling. The aqueous phase was extracted with ethyl acetate (200 mL×3).The combined organic phase was washed with brine (200 mL×3), dried withanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography (Petroleum ether/Ethylacetate=20/1, 10/1) to afford tert-butyl4,4-difluoro-5-hydroxy-pentanoate (14.2 g, 67.55 mmol, 95% yield) as acolorless oil.

Step 3: tert-butyl 4,4-difluoro-5-tetrahydropyran-2-yloxypentanoate

To a mixture of tert-butyl 4,4-difluoro-5-hydroxy-pentanoate (14.2 g,67.55 mmol, 1.00 eq) and 4-methylbenzenesulfonic acid (642 mg, 3.38mmol, 0.05 eq) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran(17.05 g, 202.65 mmol, 3.00 eq) at −10° C. under nitrogen. Then themixture was warmed to 25° C. and stirred for 16 hours. The reaction wasquenched by saturated sodium bicarbonate solution (50 mL) and thenextracted with dichloromethane (50 mL×3). The combined organic phase waswashed with brine (50 mL×3), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (Petroleum ether/Ethyl acetate=500/1, 100/1) toafford tert-butyl 4,4-difluoro-5-tetrahydropyran-2-yloxypentanoate (17.2g, crude) as a colorless oil.

Step 4: 4,4-Difluoro-5-tetrahydropyran-2-yloxy-pentan-1-ol

To a solution of lithium aluminum hydride (2.66 g, 70.12 mmol, 1.20 eq)in tetrahydrofuran (300 mL) was added a solution of tert-butyl4,4-difluoro-5-tetrahydropyran-2-yloxy-pentanoate (17.2 g, 58.44 mmol,1.00 eq) in tetrahydrofuran (60 mL) dropwise at 0° C. under nitrogenduring which the temperature was maintained below 0° C. The reactionmixture was stirred at 0° C. for 1 hour. The reaction was quenched bywater (2.6 mL), solution of sodium hydroxide in water (15%, 5.2 mL) andwater (8 mL) at 0° C. The suspension was filtered through a pad ofcelite. The cake was washed with ethyl acetate (500 mL). The combinedorganic phase was washed with brine (200 mL×3), dried over anhydroussodium sulfate, filtered and concentrated under vacuo. The residue waspurified by silica gel chromatography (Petroleum ether/Ethylacetate=20/1 to 10:1).4,4-Difluoro-5-tetrahydropyran-2-yloxy-pentan-1-ol (10.9 g, 48.61 mmol,83% yield) was obtained as a colorless oil.

Step 5:(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentyl)₄-methylbenzenesulfonate

To a mixture of 4,4-difluoro-5-tetrahydropyran-2-yloxy-pentan-1-ol (10.9g, 48.61 mmol, 1.00 eq) and p-toluenesulfonyl chloride (13.90 g, 72.91mmol, 1.50 eq) in dichloromethane (100 mL) was added triethylamine (9.84g, 97.22 mmol, 2.00 eq) in one portion at 0° C. under nitrogen. Themixture was warmed to 25° C. and stirred for 16 hours. The mixture waspoured into ice-water (w/w=1/1) (30 mL) and stirred for 15 minutes. Theaqueous phase was extracted with ethyl acetate (50 mL×3). The combinedorganic phase was washed with brine (50 mL×2), dried with anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel chromatography (Petroleum ether/Ethylacetate=20/1, 10/1) to afford(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentyl)₄-methylbenzenesulfonate(16.6 g, 43.87 mmol, 90% yield) as a colorless oil.

Step 6: Dimethyl4-(4,4-difluoro-5-hydroxy-pentoxy)benzene-1,2-dicarboxylate

To a solution of (4,4-difluoro-5-tetrahydropyran-2-yloxy-pentyl)4-methylbenzenesulfonate (1 g, 2.64 mmol, 1 eq) in N N-dimethylformamide(6 mL) was added cesium carbonate (1.72 g, 5.28 mmol, 2 eq) and dimethyl4-hydroxybenzene-1,2-dicarboxylate (555 mg, 2.64 mmol, 1 eq). Themixture was stirred at 50° C. for 12 hours. LCMS showed startingmaterial was consumed and desired compound was found. The mixture wasfiltered and poured into hydrochloric acid (1N, 30 mL), the aqueousphase was extracted with dichloromethane (20 mL×3). The combined organicphase was washed with brine (20 mL×2), dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purifiedby silica gel chromatography (Petroleum ether/Ethyl acetate=20/1, 5/1).Dimethyl 4-(4,4-difluoro-5-hydroxy-pentoxy)benzene-1,2-dicarboxylate(700 mg, 2.11 mmol, 79% yield) was obtained as a colorless oil.

Step 7: Dimethyl4-[4,4-difluoro-5-(trifluoromethylsulfonyloxy)pentoxy]benzene-1,2-dicarboxylate

To a solution of dimethyl4-(4,4-difluoro-5-hydroxy-pentoxy)benzene-1,2-dicarboxylate (600 mg,1.81 mmol, 1 eq) in dichloromethane (10 mL) was added dropwise2,6-dimethylpyridine (580 mg, 5.42 mmol, 3 eq) at 0° C. After addition,the mixture was stirred at this temperature for 10 minutes and thentrifluoromethylsulfonyl trifluoromethanesulfonate (2.55 g, 9.03 mmol, 5eq) was added dropwise at 0° C. The resulting mixture was stirred at 25°C. for 50 minutes. LCMS showed starting material was disappeared anddesired compound was found. The mixture was concentrated in vacuum. Theresidue was further purified by Pre-thin-layer chromatography (petroleumether:ethyl acetate=4:1). Dimethyl4-[4,4-difluoro-5-(trifluoromethylsulfonyloxy)pentoxy]benzene-1,2-dicarboxylate(600 mg, 1.29 mmol, 71% yield) was obtained as a white solid.

Step 8: Dimethyl4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]benzene-1,2-dicarboxylate

To a solution of dimethyl4-[4,4-difluoro-5-(trifluoromethylsulfonyloxy)pentoxy]benzene-1,2-dicarboxylate(150 mg, 0.3 mmol, 1 eq) in acetonitrile (1 mL) and dimethlysulfoxide(0.5 mL) was added potassium carbonate (133 mg, 1 mmol, 3 eq) and5-methyl-7-[6-[3-(4-piperidyloxy)cyclobutoxy]-3-pyridyl]pyrido[4,3-b]indole(138 mg, 0.3 mmol, 1 eq) [prepared as described for Compound 82]. Themixture was stirred at 50° C. for 16 hr. LCMS showed starting materialwas almost disappeared and desired compound was found. The mixture waspoured into water (20 mL) and the aqueous phase was extracted with ethylacetate (20 mL×3). The combined organic phase was washed with brine (20mL×2), dried with anhydrous sodium sulfate, filtered and concentrated invacuum. The residue was further purified by Pre-thin-layerchromatography (petroleum ether:ethyl acetate=4:1). Dimethyl4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]benzene-1,2-dicarboxylate(160 mg, 0.2 mmol, 66% yield) was obtained as a yellow oil.

Step 9:4-[4,4-Difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]phthalicacid

To a solution of dimethyl4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]benzene-1,2-dicarboxylate(120 mg, 0.16 mmol, 1 eq) in methanol (3 mL) and water (1.5 mL) wasadded potassium hydroxide (36 mg, 0.6 mmol, 4 eq). The mixture wasstirred at 55° C. for 2 hr. LCMS showed starting material was consumedand desired compound was found. The reaction mixture was adjusted topH=(7) by hydrochloric acid (1 M) and concentrated under reducedpressure to remove methanol and water. The residue was directly used fornext step without further purification.4-[4,4-Difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]phthalicacid (110 mg, 0.1 mmol, 95% yield) was obtained as a yellow solid.

Step 10:5-[4,4-Difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of4-[4,4-difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]phthalicacid (110 mg, 0.2 mmol, 1 eq) in acetic acid (2 mL) was added sodiumacetate (37 mg, 0.5 mmol, 3 eq) the mixture was stirred at 25° C. for 1hour. Then 3-aminopiperidine-2,6-dione (30 mg, 0.2 mmol, 1.2 eq,hydrochloric acid) was added into the mixture and heated to 120° C.,stirred for additional 11 hours. LCMS showed starting material wasconsumed and desired compound was found. The mixture was concentrated invacuum. The residue was purify by Pre-High Performance LiquidChromatography column: Phenomenex Synergi C18 150*25*10 um; mobilephase: [water (0.225% formic acid)-acetonitrile]; B %: 14%-35%, 7minutes.5-[4,4-Difluoro-5-[4-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]pentoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(67 mg, 0.08 mmol, 50% yield, 98% purity, formic acid) was obtained as agray solid.

¹H NMR: (400 MHz, DMSO-d₆) δ=11.11 (s, 1H), δ=9.35 (s, 1H) 6=8.64 (s,1H), 8.49-8.48 (d, J=4 Hz 1H), 8.33-8.31 (d, J=8 Hz 1H), δ=8.17 (s, 1H),δ=7.97 (s, 1H) 7.85-7.83 (d, J=8 Hz 1H), 7.62-7.61 (d, J=4 Hz 2H), 7.43(s, 1H), 6.94-6.92 (d, J=8 Hz 1H), 5.31-5.29 (m, 1H), 5.12-5.10 (m, 1H),4.34 (s, 5H), 4.25-4.23 (d, J=8 Hz 1H), 3.95 (s, 3H), 2.77 (m, 2H), 2.73(m, 4H), 2.53-2.52 (m, 1H), 2.39-2.38 (m, 4H), 1.91-1.90 (m, 4H), 1.75(m, 2H), 1.43 (m, 2H), 1.41 (m, 2H). (M+H)⁺ 807.5.

Synthetic Scheme for Exemplary Compound 164

Step 1: benzyl 6-(tosyloxy)hexanoate

To a mixture of benzyl 6-hydroxyhexanoate (1.1 g, 4.95 mmol) andtriethylamine (1.0 g, 9.90 mmol) in dichloromethane (10 ml) was added4-toluenesulfonyl chloride (1.88 g, 9.90 mmol) at 0° C. The mixture wasstirred at room temperature for 1 hour. TLC showed the reaction wascomplete. The reaction mixture was diluted with dichloromethane (20 ml),washed with brine (20 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a crude residue which waspurified by silica gel flash chromatography (eluted with 30-50% ethylacetate in hexane) to afford benzyl 6-(tosyloxy)hexanoate (960 mg, yield54%) as colorless oil.

Step 2: benzyl6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoate

A mixture of benzyl 6-(tosyloxy)hexanoate (200 mg, 0.53 mmol) and2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (146 mg, 0.53mmol), potassium carbonate (147 mg, 1.06 mmol) and potassium iodide (9mg, 0.05 mmol) in N,N-dimethylformamide (3 ml) was stirred at 50° C. for12 hours. TLC showed the reaction was complete. The reaction mixture waspartitioned between water (15 ml) and with ethyl acetate (15 ml). Theorganic layer was collected, washed with brine (10 ml), dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive a crude residue which was purified by silica gel flashchromatography (eluted with 2-5% methanol in dichloromethane) to affordbenzyl6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoate(100 mg, yield 40%) as yellow solid.

Step 3:6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoic acid

A mixture ofbenzyl6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoate(100 mg, 0.21 mmol) and palladium on activated carbon (20%, 50 mg) inmethanol (2 ml) was stirred at room temperature for 1 hour underhydrogen atmosphere (hydrogen balloon). TLC showed the reaction wascomplete. The reaction mixture was filtered, and concentrated underreduced pressure to afford6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoic acid(70 mg, yield 86%) as yellow oil which was used in next step directlywithout further purification.

Step 4: 5-(6-(4-((1r,3r)-3-(5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yloxy)cyclobutoxy)piperidin-1-yl)-6-oxohexyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a mixture of6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yloxy)hexanoic acid(70 mg, 0.18 mmol) and 7-(6-((1r,3r)-3-(piperidin-4-yloxy)cyclobutoxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole(75 mg, 0.18 mmol) [prepared as described in Compound 65] andtriethylamine (56 mg, 0.56 mmol) in N,N-dimethylformamide (2 ml) wasadded (2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (212 mg, 0.56 mmol) at room temperature. Themixture was stirred at room temperature for 1 hour. TLC showed thereaction was complete. The reaction mixture was diluted withdichloromethane (50 ml), washed with brine (50 ml), dried over anhydroussodium sulfate, and concentrated under reduced pressure to give a cruderesidue which was purified by silica gel flash chromatography (elutedwith 2-5% methanol in dichloromethane) to afford the title compound (6.6mg, yield 5%) as white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.52-1.57 (m, 3H), 1.61-1.65 (m, 2H),1.70-1.74 (m, 2H), 1.98-2.01 (m, 2H), 2.13-2.17 (m, 1H), 2.34-2.41 (m,2H), 2.47-2.50 (m, 2H), 2.78-2.88 (m, 2H), 3.20-3.28 (m, 2H), 3.54-3.72(m, 3H), 4.00-4.10 (m, 3H), 4.39-4.44 (m, 1H), 4.95 (dd, J=5.2, 12.0 Hz,1H), 5.31-5.42 (m, 4H), 6.82 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H),7.31-7.34 (m, 2H), 7.48-7.51 (m, 2H), 7.68 (s, 1H), 7.77 (d, J=8.8 Hz,1H), 7.87 (d, J=7.2 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.32 (s, 1H),8.41-8.45 (m, 2H), 9.23 (s, 1H).

Synthetic Scheme for Exemplary Compounds 198 and 205

2-(2,6-dioxopiperidin-3-yl)-5-((3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)prop-2-yn-1-yl)oxy)isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)phenyl)propoxy)isoindoline-1,3-dione

Compounds 198 and 205 were prepared according to the synthetic schemebelow using procedures described above and common procedures known tothose skilled in the art:

Synthetic Scheme for Exemplary Compound 68

2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)piperazin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 9.37 (s, 1H), 8.64 (s, 1H),8.50 (d, J=4.0 Hz, 1H), 8.33 (d, J=12.0 Hz, 1H), 8.00 (s, 1H), 7.68-7.60(m, 3H), 7.34 (d, J=4.0 Hz, 1H), 7.25 (dd, J 8.0 Hz, 4.0 Hz, 1H), 6.94(d, J 8.0 Hz, 1H), 5.32 (t, J 4.0 Hz, 1H), 5.07 (dd, J 12.0 Hz, 8.0 Hz,1H), 4.20-4.17 (m, 1H), 3.96 (s, 3H), 4.46 (s, 6H), 2.88-2.84 (m, 1H),2.59-2.54 (m, 7H), 2.43-2.32 (m, 6H), 2.02-1.98 (m, 1H), 1.57-1.49 (m,4H), 1.38-1.34 (m, 2H). (M+H)+756.6

Synthetic Scheme for Exemplary Compound 70

2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione

Step 1: 2-((1r, 3r)-3-(benzyloxy)cyclobutoxy)-5-bromopyridine

To a solution of (1r, 3r)-3-(benzyloxy)cyclobutan-1-ol (500 mg, 2.8mmol) in DMF (15 mL) was added NaH (336 mg, 8.4 mmol, 60%) at 0° C. Thesolution was stirred at 0° C. for 30 minutes. 5-bromo-2-fluoropyridine(1.0 g, 5.6 mmol) in DMF (3 mL) was added. The resulting solution washeated at 80° C. overnight. After cooling to room temperature, themixture was quenched with water. The mixture was extracted with ethylacetate, and the organic layer was washed with water and brine. Theorganic phase was dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel (PE:EA=100:1) to afford the desiredcompound (630 mg, 67% yield) as a colorless oil.

Step 2: (1r, 3r)-3-((5-bromopyridin-2-yl)oxy)cyclobutan-1-ol

To a solution of 2-((1r, 3r)-3-(benzyloxy)cyclobutoxy)-5-bromopyridine(630 mg, 1.88 mmol) in DCM (15 mL) was added BBr₃ (1.42 g, 5.65 mmol) at−78° C. The resulting solution was stirred at −78° C. for 0.5 hours. Thesolution was quenched with NaHCO₃. The layers were separated and theaqueous layer was extracted with DCM. The combined organic layers wereconcentrated to afford the desired compound (390 mg, crude) as a yellowsolid, which was used directly in the next step without furtherpurification.

Step 3: 5-bromo-2-((1r,3r)-3-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)cyclobutoxy)pyridine

To a solution of (1r, 3r)-3-((5-bromopyridin-2-yl)oxy)cyclobutan-1-ol(390 mg, 1.64 mmol) in THF (15 mL) was added NaH (262 mg, 60%) at 0° C.The solution was stirred at 10° C. for 0.5 hours, and then13-bromo-1-phenyl-2,5,8,11-tetraoxatridecane (570 mg, 1.64 mmol) wasadded. The resulting solution was stirred at 70° C. for 20 hours. Thesolution was quenched with water. The layers were separated and theaqueous layer was extracted with EA. The combined organic layers werewashed with brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel with PE:EA (1:1) to afford the desired compound (350 mg) as ayellow solid.

5-bromo-2-((1r,3r)-3-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)cyclobutoxy)pyridinewas converted to the final compound,2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione,according to the following scheme and using procedures described aboveand common procedures known to those skilled in the art.

Compound 70: ¹H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.36 (s, 1H),8.62 (s, 1H), 8.50 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.18 (d, J=8.8 Hz,1H), 7.97 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.43(s, 1H), 7.35 (d, J=7.8 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 5.31 (s, 1H),5.11 (dd, J=12.8, 5.1 Hz, 1H), 4.31 (s, 2H), 4.22 (s, 1H), 3.95 (s, 3H),3.79 (s, 2H), 3.64-3.48 (m, 10H), 3.45 (d, J=4.9 Hz, 3H), 2.86 (d,J=13.2 Hz, 1H), 2.45-2.40 (m, 2H), 2.37-2.30 (m, 2H), 2.02 (d, J=6.5 Hz,1H). (M+H)⁺ 778.5.

Synthetic Scheme for Exemplary Compound 71

2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-yl)oxy)isoindoline-1,3-dione

Step 1: 15-(5-bromopyridin-2-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-ol

To a solution of 3,6,9,12-tetraoxapentadec-14-yn-1-ol (570 mg, 2.45mmol) in dried THF (10 mL) were added 2,5-dibromopyridine (697.6 mg,2.94 mmol), CuI (51.4 mg, 0.27 mmol) and Pd(PPh₃)₂Cl₂ (80 mg, 0.24 mmol)at 15° C. under N2 atmosphere subsequently. The solution was stirred at40° C. for 1.5 hours. The solution was quenched with H₂O (10 mL) and themixture was extracted with EtOAc (10 mL×2). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by silica gel columnchromatography to afford the desired compound (530 mg, 56% yield) as ayellow oil.

15-(5-bromopyridin-2-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-ol wasconverted to the final compound,2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-yl)oxy)isoindoline-1,3-dione,according to the following scheme and using procedures described aboveand common procedures known to those skilled in the art.

Compound 71: ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.38 (d, J=8.4Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.28 (d, J=3.0 Hz, 1H), 8.11 (s, 1H),7.80 (d, J=8.4 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.63-7.68 (m, 2H), 7.44(d, J=2.0 Hz, 1H), 7.34-7.36 (m, 1H), 5.08-5.12 (m, 1H), 4.48 (s, 2H),4.31 (t, J=3.6 Hz, 2H), 3.98 (s, 3H), 3.80 (s, 3H), 3.53-3.79 (m, 12H),1.95-2.08 (m, 2H). (M+H)⁺ 746.5.

Synthetic Scheme for Exemplary Compound 74

2-(2,6-dioxopiperidin-3-yl)-5-((15-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 74: ¹H NMR (400 MHz, CDCl₃): δ 9.65 (s, 1H), 9.22 (s, 1H),8.67-8.73 (m, 2H), 8.47 (d, J=7.6 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H), 7.97(s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.59-7.71 (m, 2H), 7.04 (d, J=9.2Hz, 2H), 4.93-4.96 (m, 1H), 4.10 (s, 5H), 3.87 (s, 1H), 3.55-3.76 (m,18H), 3.26 (s, 2H), 2.12-2.16 (m, 2H). (M+H)⁺ 750.5.

Synthetic Scheme for Exemplary Compound 72

5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-4,6,7-trifluoroisoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

2-(2,6-dioxopiperidin-3-yl)-4,5,7-trifluoro-6-hydroxyisoindoline-1,3-dionewas prepared as described below.

Step 1: 3,4,6-trifluoro-5-hydroxyphthalic acid

To a solution of 3,4,5,6-tetrafluorophthalic acid (1.18 g, 5 mmol) inwater (20 mL) was added potassium hydroxide (2.24 g, 40 mmol, 8 eq). Theresulting solution was heated to 90° C. for 9 hours. Then the reactionwas cooled to room temperature and neutralized by HCl (1 N). Theresulting solution was extracted with ethyl acetate (50 mL×3). Thecombined organic layers were washed with brine (20 mL×2), dried overanhydrous sodium sulfate and concentrated under vacuum to afford crudedesired product (1.15 g) as white solid, which was used in the next stepwithout purification.

Step 2:2-(2,6-dioxopiperidin-3-yl)-4,5,7-trifluoro-6-hydroxyisoindoline-1,3-dione

To a solution of 3,4,6-trifluoro-5-hydroxyphthalic acid (500 mg, 2.12mmol), 3-aminopiperidine-2,6-dione (383 mg, 2.33 mmol) in AcOH was addedAcONa (209 mg, 2.54 mmol). The resulting solution was stirred at 120° C.for 4 h. After cooling to room temperature, the solvent was removedunder vacuum. Then it was quenched with water (30 mL). The resultingsolution was extracted with EA (30 mL×3). The combined organic layerswere washed with brine (10 mL×2), dried over anhydrous sodium sulfateand concentrated under vacuum to afford2-(2,6-dioxopiperidin-3-yl)-4,5,7-trifluoro-6-hydroxyisoindoline-1,3-dione(400 mg, 1.22 mmol, 58%).

Compound 72: ¹H NMR (400 MHz, CD₃OD): δ 13.19 (s, 1H), 9.77 (s, 1H),8.62-8.68 (m, 2H), 8.52 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 8.01-8.02 (m,2H), 7.80-7.81 (m, 1H), 7.15-7.28 (m, 1H), 6.99 (d, J=8.0 Hz, 1H),5.15-5.23 (m, 1H), 4.43-4.45 (m, 2H), 3.77-3.89 (m, 4H), 3.49-3.60 (m,12H), 2.86-3.05 (m, 3H), 1.99-2.01 (m, 1H). (M+H)⁺ 792.5.

Synthetic Scheme for Exemplary Compound 81

5-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 81: ¹H NMR (400 MHz, CDCl₃): δ 9.31 (s, 1H), 8.51 (s, 1H), 8.40(s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.82-7.83 (m, 1H), 7.60 (s, 1H),7.37-7.45 (m, 3H), 6.84 (d, J=8.0 Hz, 1H), 4.92-4.95 (m, 1H), 4.53 (t,J=4.8 Hz, 2H), 4.24 (t, J=4.8 Hz, 2H), 3.89-3.91 (m, 4H), 3.67-3.75 (m,12H), 2.74-2.92 (m, 3H), 2.12-2.16 (m, 1H). (M+H)⁺ 756.5.

Synthetic Scheme of Exemplary Compound 75

2-(2,6-dioxopiperidin-3-yl)-5-(4-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)piperidin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 75: ¹H NMR (400 MHz, DMSO-d₆): δ=11.07 (s, 1H), 9.38-9.32 (m,1H), 8.66-8.63 (d, J=12 Hz 1H), 8.50-8.48 (m, J=8 Hz 1H), 8.36 (s, 2H),8.34-8.29 (m, 1H), 8.21-8.14 (m, 1H), 7.99-7.94 (m, 1H), 7.61 (s, 3H),7.28-7.22 (m, 1H), 7.19-7.12 (m, 1H), 6.96-6.89 (m, 1H), 5.09-5.00 (m,1H), 4.36-4.29 (m, 2H), 3.95 (s, 5H), 3.34 (s, 4H), 2.87 (s, 2H),2.99-2.78 (m, 1H), 2.82-2.73 (m, 1H), 2.04-1.93 (m, 1H), 1.82-1.65 (m,4H), 1.61-1.52 (m, 2H), 1.52-1.41 (m, 5H), 1.28 (s, 4H), 1.22-1.05 (m,4H). (M+H)⁺ 771.6.

Synthetic Scheme for Exemplary Compound 76

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(3-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures to those skilled in the art.

Compound 76: ¹H NMR (400 MHz, CD₃OD): δ 9.32 (s, 1H), 8.96 (s, 1H),8.45-8.52 (m, 2H), 8.37 (d, J=8.0 Hz, 1H), 8.27-8.31 (m, 1H), 7.98 (s,1H), 7.61-7.98 (m, 4H), 6.82 (s, 1H), 6.65-6.67 (m, 1H), 5.01-5.05 (m,1H), 4.59 (m, 1H), 4.27 (t, J=8.4 Hz, 1H), 4.02 (s, 3H), 3.88-3.91 (m,2H), 3.70 (s, 2H), 3.57 (t, J=6.0 Hz, 2H), 3.41 (m, 1H), 3.13-3.17 (m,2H), 2.66-2.86 (m, 11H), 2.02-2.03 (m, 3H). (M+H)⁺ 751.5.

Synthetic Scheme for Exemplary Compound 78

2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)piperazin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 78: ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.35 (s, 1H),8.64 (t, J=3.9 Hz, 1H), 8.49 (d, J=4.7 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H),8.19 (dd, J=8.6, 2.5 Hz, 1H), 7.98 (s, 1H), 7.68-7.48 (m, 3H), 7.31 (d,J=7.8 Hz, 1H), 7.20 (t, J=9.5 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 5.07 (dd,J=12.9, 5.3 Hz, 1H), 4.33 (t, J=6.5 Hz, 2H), 3.95 (s, 3H), 3.65 (m, 1H),3.51-3.41 (m, 3H), 3.36-3.23 (m, 5H), 2.95-2.83 (m, 1H), 2.43-2.28 (m,6H), 2.05-1.96 (m, 1H), 1.79-1.73 (m, 1H), 1.67-1.61 (m, 1H), 1.42 (m,7H). (M+H)⁺ 770.6.

Synthetic Scheme of Exemplary Compound 85

2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)cyclobutoxy)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 85: ¹H NMR (400 MHz, CDCl₃): δ 9.32 (s, 1H), 8.58-8.59 (d,J=4.0 Hz, 2H), 8.48 (s, 1H), 8.16-8.18 (d, J=8.0 Hz, 1H), 7.89-7.91 (d,J=8.0 Hz, 1H), 7.74-7.76 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.47-7.49 (d,J=8.0 Hz, 1H), 7.32-7.33 (d, J=4.0 Hz, 1H), 7.19 (s, 1H), 7.06-7.08 (d,J=8.0 Hz, 1H), 6.84-6.86 (d, J=8.0 Hz, 1H), 4.93 (m, 2H), 4.35-4.38 (m,2H), 4.21 (s, 1H), 3.90 (s, 3H), 3.35-3.49 (m, 7H), 2.68-2.95 (m, 3H),2.44-2.51 (m, 4H), 2.15 (m, 1H), 1.88 (m, 2H), 1.56-1.68 (m, 9H), 1.44(d, J=8.0 Hz, 2H). (M+H)⁺ 774.6.

Synthetic Scheme of Exemplary Compound 79

2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)oxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 79: ¹H NMR (400 MHz, CDCl₃): δ 9.35 (s, 1H), 8.59 (d, J=5.7 Hz,1H), 8.49 (s, 1H), 8.28 (s, 1H), 8.21 (d, J=10.6 Hz, 1H), 8.00 (s, 1H),7.91 (d, J=11.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.57 (s, 1H), 7.51 (d,J=9.3 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.77 (s,1H), 4.92 (m, 1H), 4.45 (s, 1H), 4.36 (t, J=6.6 Hz, 2H), 4.16-4.26 (m,2H), 3.83-3.98 (m, 4H), 3.44 (m, 4H), 2.63-2.92 (m, 3H), 2.11 (d, J=6.4Hz, 2H), 1.79-1.89 (m, 3H), 1.44-1.70 (m, 10H). (M+H)⁺ 759.6.

Synthetic Scheme for Exemplary Compound 80

2-(2,6-dioxopiperidin-3-yl)-5-((1-(5-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)pentyl)azetidin-3-yl)oxy)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 80: ¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (s, 1H), 9.35 (s, 1H),8.63 (d, J=2.3 Hz, 1H), 8.50 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.18 (dd,J=8.6, 2.5 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.60 (d, J=6.8Hz, 2H), 7.23 (d, J=7.2 Hz, 2H), 6.93 (d, J=8.6 Hz, 1H), 5.10 (m, 1H),5.02-4.95 (m, 1H), 4.32 (t, J=6.6 Hz, 2H), 3.95 (s, 3H), 3.70 (t, J=6.8Hz, 2H), 2.99-2.95 (m, 2H), 2.86 (d, J=12.1 Hz, 2H), 2.64 (br, 1H), 2.55(br, 2H), 2.33 (s, 2H), 2.06-1.96 (m, 3H), 1.81-1.70 (m, 3H), 1.60-1.40(m, 8H). (M+H)⁺ 759.6.

Synthetic Scheme for Exemplary Compound 84

2-(2,6-dioxopiperidin-3-yl)-5-((6-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenoxy)hexyl)oxy)isoindoline-1,3-dione

Step 1: 2-((6-(3-(benzyloxy)phenoxy)hexyl)oxy)tetrahydro-2H-pyran

A solution of 3-(benzyloxy)phenol (1.13 g, 5.66 mmol),2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (1.0 g, 3.77 mmol) and Cs₂CO₃(2.45 g, 7.55 mmol) in acetone (30 mL) was stirred at 70° C. overnight.The mixture was cooled to room temperature and quenched with water. Themixture was extracted with EA (200 mL), and the solution was washed withwater (30 mL×3) and brine (30 mL). The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified to afford the desired product (PE:EA=20:1) (1.2 g, yield=83%)as colorless oil.

Step 2: 3-((6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)oxy)phenol

To a solution of2-((6-(3-(benzyloxy)phenoxy)hexyl)oxy)tetrahydro-2H-pyran (1.2 g, 3.13mmol) in MeOH (30 mL) was added Pd/C (200 mg) at room temperature. Theresulting solution was stirred at room temperature overnight under H₂ 1atm. The mixture was filtered, the filtrate was concentrated undervacuum to afford crude desired product (900 mg) as light yellow oil,which was used in the next step directly.

Step 3: 2-((6-(3-((1r,3r)-3-(benzyloxy)cyclobutoxy)phenoxy)hexyl)oxy)tetrahydro-2H-pyran

To a solution of 3-((6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)oxy)phenol(100 mg, 0.34 mmol), (1s, 3s)-3-(benzyloxy)cyclobutanol (91 mg, 0.51mmol), PPh₃ (267 mg, 1.02 mmol) in THF (5.0 mL) were added DIAD (206 mg,1.02 mmol) at 40° C. under a nitrogen atmosphere. The resulting mixturewas heated to 80° C. overnight. After cooling to room temperature, thereaction was quenched with water. The mixture was extracted with EA (50mL), and the organic phase was washed with water (20 mL×3), brine (20mL), dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified to afford the desired product (PE:EA=5:1) (130mg, yield=84%) as colorless oil.

2-((6-(3-((1r,3r)-3-(benzyloxy)cyclobutoxy)phenoxy)hexyl)oxy)tetrahydro-2H-pyran wasconverted into the final compound,2-(2,6-dioxopiperidin-3-yl)-5-((6-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)phenoxy)hexyl)oxy)isoindoline-1,3-dione,according to the synthetic scheme below using procedures described aboveand common procedures known to those skilled in the art.

Compound 84: 1H NMR (400 MHz, CDCl₃): δ 93.4 (s, 1H), 8.58 (d, J=5.6 Hz,1H), 8.21-8.48 (m, 2H), 8.20 (d, J=8.4 Hz, 1H), 7.88-7.91 (m, 1H), 7.76(d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.33-7.36 (m,2H), 7.16-7.18 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.39-6.51 (m, 3H),5.52-5.54 (m, 1H), 4.94-4.96 (m, 2H), 4.07-4.10 (m, 2H), 3.91-3.97 (m,5H), 3.22-3.24 (m, 1H), 2.69-2.76 (m, 7H), 2.14-2.16 (m, 1H), 1.82-1.86(m, 4H), 1.54-1.57 (m, 4H). (M+H)⁺ 794.5.

Synthetic Scheme for Exemplary Compound 86

4-((14-(4-(5H-pyrido[4,3-b]indol-7-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 86: ¹H NMR (400 MHz, CDCl₃): δ 9.28 (s, 2H), 8.50 (s, 1H), 8.08(s, 1H), 7.35-7.57 (m, 6H), 6.94-6.96 (m, 3H), 6.77 (s, 1H), 6.38 (s,1H), 4.88-4.90 (m, 1H), 4.14 (s, 2H), 3.60-3.86 (m, 17H), 3.31-3.34 (m,2H), 2.66-2.86 (m, 3H), 2.03-2.05 (m, 1H). (M+H)⁺ 736.5.

Synthetic Schedule for Exemplary Compound 87

6-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione

Step 1:6-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)pyridine-3,4-dicarboxylicacid

To a solution of14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol(200.0 mg, 0.42 mmol) and 6-chloropyridine-3,4-dicarboxylic acid (166mg, 0.83 mmol) in anhydrous tetrahydrofuran (4 mL) was added sodiumhydride (162.0 mg, 4.2 mmol). The resulting solution was stirred at 100°C. with MW for 2 hour under N2 atmosphere. The solution was cooled toroom temperature and quenched with water (20 mL). The mixture wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (20 mL×2). The organic layer was dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel column chromatography to afford the desiredcompound (50 mg, 0.077 mmol, 9% yield).

Step 2:6-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione

To a solution of6-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)pyridine-3,4-dicarboxylicacid (50 mg, 0.077 mmol) and 3-aminopiperidine-2,6-dione (12 mg, 0.092mmol) in AcOH (6 mL) was added NaOAc (6 mg, 0.092 mmol). The resultingsolution was stirred at 120° C. for 16 hours. After cooling to roomtemperature, the reaction was quenched by the addition of water (20 mL).The mixture was extracted with EA (20 mL×3). The combined organic layerswere washed with brine (20 mL×2), dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by prep-TLC withDCM/CH₃OH (10:1) to afford the title compound (4.0 mg, 0.005 mmol, 7%yield).

Compound 87: ¹H NMR (400 MHz, CDCl₃): δ 9.28 (s, 1H), 8.42 (s, 1H),8.37-8.39 (m, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.62(s, 1H), 7.40-7.45 (m, 3H), 6.09 (s, 1H), 6.82 (d, J=8.8 Hz, 1H),4.94-4.99 (m, 1H), 4.54 (t, J=4.8 Hz, 4H), 3.86-3.91 (m, 4H), 3.66-3.75(m, 12H), 2.73-2.92 (m, 3H), 2.20-2.22 (m, 1H). (M+H)⁺ 739.5.

Synthetic Scheme for Exemplary Compound 88

2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-(2,2,2-trifluoroethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 88: ¹H NMR (400 MHz, CDCl₃): δ 9.35 (s, 1H), 8.63 (d, J=7.6 Hz,1H), 8.45 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 7.87-7.90 (m,1H), 7.75 (d, J=8.4 Hz, 1H), 7.53-7.58 (m, 2H), 7.39 (s, 1H), 7.35 (s,1H), 7.21 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.87-4.92 (m, 3H),4.55 (t, J=4.8 Hz, 2H), 4.24 (t, J=4.8 Hz, 2H), 3.90 (t, J=4.4 Hz, 3H),3.66-3.73 (m, 12H), 2.76-2.87 (m, 3H), 2.09-2.16 (m, 1H). (M+H)⁺ 820.5

Synthetic Scheme for Exemplary Compound 89

2-(2,6-dioxopiperidin-3-yl)-5-(4-(3,3,3-trifluoro-2-(2-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)ethoxy)propyl)piperidin-1-yl)isoindoline-1,3-dione

Step 1: 2-(5-benzyloxypentoxy)acetate

To a solution of 5-benzyloxypentan-1-ol (1 g, 5.15 mmol, 1.0 eq) indichloromethane (20 mL) was added ethyl 2-diazoacetate (704 mg, 6.18mmol, 1.2 eq) and dirhodium tetraacetate (11 mg, 0.03 mmol). Then themixture was stirred at 20° C. for 0.5 hour. The mixture was quenchedwith ethyl alcohol (10 mL) and then concentrated. The residue waspurified by silica column chromatography (petroleum ether; ethylacetate=50:1 to 4:1) to afford ethyl 2-(5-benzyloxypentoxy)acetate (700mg, 2.50 mmol, 49% yield) as a yellow oil.

Step 2: 2-(5-benzyloxypentoxy)ethanol

To a mixture of LiAlH₄ (189 mg, 4.99 mmol, 2.0 eq) in tetrahydrofuran (4mL) was added a solution of ethyl 2-(5-benzyloxypentoxy)acetate (700 mg,2.50 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at 0° C. Then the mixturewas stirred at 20° C. for 2 hours. The mixture was quenched with water(0.2 mL), aqueous sodium hydroxide (1 M, 0.2 mL), and more water (0.8mL). Then filtered and concentrated. The residue was purified by silicacolumn chromatography (petroleum ether: ethyl acetate=30:1 to 10:1) toafford 2-(5-benzyloxypentoxy)ethanol (400 mg, 1.68 mmol, 67% yield) wasobtained as a white oil.

Step 3: 2-(5-benzyloxypentoxy)ethyl4-methylbenzenesulfonate

To a mixture of 2-(5-benzyloxypentoxy)ethanol (400 mg, 1.68 mmol, 1.0eq) and toluene sulfonyl chloride (640 mg, 3.36 mmol, 2.0 eq) intetrahydrofuran (3 mL) was added potassium hydroxide (2.83 g, 50.35mmol, 30.0 eq). Then the mixture was stirred at 20° C. for 0.5 hour. Themixture was diluted with water (10 mL), extracted with ethyl acetate (20mL), washed with brine (20 mL), dried over anhydrous sodium sulfate andthen concentrated. The mixture was purified by silica columnchromatography (petroleum ether: ethyl acetate=30:1 to 10:1) to afford2-(5-benzyloxypentoxy)ethyl4-methylbenzenesulfonate (570 mg, 1.45 mmol,86% yield) as a white oil.

Step 4: tert-butyl 4-(3,3,3-trifluoro-2-hydroxy-propyl)piperidine-1-carboxylate

To a mixture of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1.9g, 8.36 mmol, 1.0 eq) and trimethyl(trifluoromethyl)silane (1.43 g,10.03 mmol, 1.2 eq) in tetrahydrofuran (20 mL) was addedtetrabutylammonium fluoride (1 M, 0.1 mL) at 0° C. Then the mixture wasstirred at 20° C. for 1 hour. Then aqueous hydrochloric acid (1 M, 17mL, 2.0 eq) was added into the mixture and stirred at 20° C. foradditional 2 hours. The mixture was extracted with dichloromethane (100mL), washed with brine (50 mL), dried over anhydrous sodium sulfate andthen concentrated. The residue was purified by silica columnchromatography (petroleum ether:ethyl acetate=100:1 to 10:1) to affordtert-butyl 4-(3,3,3-trifluoro-2-hydroxy-propyl) piperidine-1-carboxylate(2.0 g, 6.73 mmol, 80% yield) as a white solid.

Step 5:tert-butyl4-[2-[2-(5-benzyloxypentoxy)ethoxy]-3,3,3-trifluoro-propyl]piperidine-1-carboxylate

To a solution of tert-butyl4-(3,3,3-trifluoro-2-hydroxy-propyl)piperidine-1-carboxylate (216 mg,0.73 mmol, 1.0 eq) in dimethyl formamide (2 mL) was added sodium hydride(58 mg, 1.46 mmol, 60% in mineral oil, 2.0 eq) at 15° C. Then themixture was stirred at 15° C. for 0.5 hour under nitrogen.2-(5-benzyloxypentoxy)ethyl 4-methylbenzenesulfonate (200 mg, 0.51 mmol,0.7 eq) was added into the mixture and stirred at 50° C. for additional2.5 hours. The mixture was quenched with water (5 mL), extracted withethyl acetate (20 mL×2), washed with brine (20 mL), dried over anhydroussodium sulfate and then concentrated. The mixture was purified by silicacolumn chromatography (petroleum ether:ethyl acetate=200:1 to 10:1) toaffordtert-butyl4-[2-[2-(5-benzyloxypentoxy)ethoxy]-3,3,3-trifluoro-propyl]piperidine-1-carboxylate(300 mg, 0.58 mmol, 80% yield) as a white oil.

Tert-butyl4-[2-[2-(5-benzyloxypentoxy)ethoxy]-3,3,3-trifluoro-propyl]piperidine-1-carboxylatewas converted to the title compound,2-(2,6-dioxopiperidin-3-yl)-5-(4-(3,3,3-trifluoro-2-(2-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)ethoxy)propyl)piperidin-1-yl)isoindoline-1,3-dione,according to the synthetic scheme below using procedures described aboveand common procedures known to those skilled in the art.

Compound 8: ¹H NMR (400 MHz, DMSO-d₆) δ: 11.09 (s, 1H), 9.36 (s, 1H),8.61 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H),8.21 (s, 1H), 8.15 (dd, J=2.8, 8.8 Hz, 1H), 7.95 (s, 1H), 7.65-7.57 (m,3H), 7.29 (s, 1H), 7.23-7.18 (m, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.04 (dd,J=5.6, 12.8 Hz, 1H), 4.31 (t, J=6.4 Hz, 2H), 4.14 (br s, 1H), 4.10-3.99(m, 3H), 3.96 (s, 3H), 3.87 (d, J=11.6 Hz, 2H), 3.74 (dd, J=5.6, 10.8Hz, 2H), 3.02-2.81 (m, 4H), 1.98-1.86 (m, 2H), 1.85-1.72 (m, 4H),1.63-1.15 (m, 9H). (M+H)⁺ 841.6.

Synthetic Scheme for Exemplary Compound 90

2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-((4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)but-2-yn-1-yl)oxy)butoxy)butoxy)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 90: ¹HNMR (400 MHz, CDCl₃): δ 9.35 (s, 1H), 8.60 (s, 1H), 8.50(s, 1H), 8.20 (d, J=8.0 Hz, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.55 (s, 1H),7.49 (d, J=8.0 Hz, 1H), 7.32 (d, J=10.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 1H),6.92 (d, J=8.4 Hz, 1H), 5.10 (s, 2H), 4.98-5.00 (m, 1H), 4.21 (s, 2H),4.07-4.10 (m, 2H), 3.90 (s, 3H), 3.44-3.54 (m, 7H), 2.76-2.87 (m, 3H),2.18-2.23 (m, 2H), 1.88-1.92 (m, 3H), 1.72-1.75 (m, 4H). M+H)⁺ 744.5.

Synthetic Scheme for Exemplary Compound 91

2-(2,6-dioxopiperidin-3-yl)-5-(4-(8-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)octyl)piperazin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 91: 1H NMR (400 MHz, CD₃OD): δ 9.33 (s, 1H), 8.51-8.53 (m, 2H),8.33-8.34 (m, 1H), 8.09-8.11 (m, 1H), 7.84 (s, 1H), 7.59-7.62 (m, 3H),7.30 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.32-5.35(m, 1H), 3.99 (s, 3H), 3.40-3.47 (m, 13H), 2.69-2.71 (m, 6H), 2.50-2.52(m, 4H), 2.03-2.18 (m, 5H), 1.59-1.60 (m, 6H). (M+H)⁺ 798.6.

Synthetic Scheme for Exemplary Compound 92

5-((14-((3-chloro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 92: ¹H NMR (400 MHz, CDCl₃): δ 9.32 (s, 1H), 8.68 (s, 1H), 8.58(s, 1H), 8.35 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.74 (d,J=8.4 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.27-7.34 (m, 2H),7.20 (d, J=7.6 Hz, 1H), 4.92-4.96 (m, 1H), 4.61 (s, 2H), 4.23 (s, 2H),3.89-3.94 (m, 8H), 3.68-3.78 (m, 11H), 2.72-2.90 (m, 3H), 2.01-2.12 (m,1H). (M+H)⁺ 786.5, 788.5.

Synthetic Scheme for Exemplary Compound 93

5-((6-((5-(2,2-difluoro-2-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)ethoxy)pentyl)oxy)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 93: ¹H NMR (400 MHz, CDCl₃): δ 9.35 (br, 1H), 8.94 (s, 1H),8.59 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.01-8.09 (m, 2H), 7.73 (d, J=8.4Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J=8.4 Hz, 1H),7.31 (d, J=5.2 Hz, 1H), 7.24 (s, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H),4.85-4.90 (m, 1H), 4.10 (t, J=8.0 Hz, 1H), 3.98 (t, J=6.4 Hz, 1H), 3.87(s, 3H), 3.51 (t, J=6.4 Hz, 1H), 3.27-3.32 (m, 4H), 2.65-2.85 (m, 3H),2.04-2.08 (m, 1H), 1.71-1.76 (m, 4H), 1.45-1.52 (m, 8H), 0.75-0.85 (m,4H). (M+H)⁺ 782.5.

Synthetic Scheme for Exemplary Compound 96

2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)-3-(trifluoromethyl)piperazin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic schemes below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 96: ¹H NMR: 400 MHz, DMSO-d6 δ: 11.09 (s, 1H), 9.38 (s, 1H),8.64 (d, J=2.4 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H),8.19 (dd, J=2.4, 8.8 Hz, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.72-7.59 (m,3H), 7.21 (d, J=2.0 Hz, 1H), 7.12 (dd, J=2.0, 8.8 Hz, 1H), 6.94 (d,J=8.4 Hz, 1H), 5.38-5.26 (m, 1H), 5.06 (dd, J=5.3, 12.9 Hz, 1H),4.24-4.13 (m, 1H), 3.96 (s, 3H), 3.95-3.88 (m, 1H), 3.72 (d, J=15.2 Hz,1H), 3.68-3.63 (m, 1H), 3.53 (d, J=7.2 Hz, 1H), 3.31 (s, 2H), 3.07-2.75(m, 4H), 2.74-2.54 (m, 4H), 2.44-2.29 (m, 4H), 2.06-1.94 (m, 1H), 1.50(td, J=7.0, 13.8 Hz, 4H), 1.33 (s, 4H). (M+H)⁺ 838.6.

Synthetic Scheme for Exemplary Compound 99

2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione

Step 1: 2-(3-bromopropoxy)tetrahydro-2H-pyran

A mixture of 3-bromopropan-1-ol (5.56 g, 40 mmol), dihydropyran (4.0 g,48 mmol) and p-toluenesulfonic acid (0.76 g, 4 mmol) in tetrahydrofuran(80 ml) was stirred at room temperature overnight. The reaction mixturewas quenched with aqueous sodium bicarbonate solution (sat. 10 ml) andextracted with tert-butyl methyl ether (50 ml×3). The combined organiclayers were washed with brine (50 ml), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give a crude residuewhich was purified by silica gel flash chromatography (eluted 10% ethylacetate in hexane) to afford 2-(3-bromopropoxy)tetrahydro-2H-pyran (6.4g, yield 72%) as colorless oil.

Step 2: 3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propan-1-ol

To a solution of propane-1,3-diol (4.6 g, 60 mmol) inN,N-dimethylformamide (50 ml) was added sodium hydride (60% in mineraloil) (0.88 g, 222 mmol) at 0° C., and the resulting mixture was stirredat 0° C. for 30 minutes. To the reaction mixture was added2-(3-bromopropoxy)tetrahydro-2H-pyran (2.2 g, 20 mmol), and theresulting reaction mixture was stirred at 65° C. for 16 hours. Thereaction mixture was quenched with water (150 ml) at 0° C. and extractedwith ethyl acetate (200 ml×2). The combined organic layers were washedwith brine (50 ml×2), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a residue which was purifiedby silica gel flash chromatography (eluted with 30% ethyl acetate inhexane) to afford3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propan-1-ol (0.9 g, yield45%) as colorless oil.

Step 3: 3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propyl4-methylbenzenesulfonate

To a stirred solution of3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propan-1-ol (900 mg, 4.1mmol), triethylamine (1.1 ml, 8.25 mmol) in dichloromethane (30 ml) wasadded tosyl chloride (0.94 g, 4.95 mmol) and 4-dimethylaminopyridine (50mg, 0.4 mmol) at 0° C. The resulting solution was allowed to warm up toroom temperature and stirred at room temperature for 2 hours. Themixture was poured into water (20 ml) and extracted with dichloromethane(20 ml×2). The combined organic layers were washed with brine (20 ml),dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give a crude residue which was purified by silica gel flashcolumn chromatography (eluted with 10-20% ethyl acetate in hexane) toafford 3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propyl4-methylbenzenesulfonate (1.2 g, yield 78%) as colorless oil.

Step 4: 2-(3-(3-((1r,3r)-3-(benzyloxy)cyclobutoxy)propoxy)propoxy)tetrahydro-2H-pyran

To a solution of (1r, 3r)-3-(benzyloxy)cyclobutanol (200 mg, 1.12 mmol)in N,N-dimethylformamide (6 ml) was added sodium hydride (60% in mineraloil) (63 mg, 1.57 mmol) at 0° C., and the resulting mixture was stirredat room temperature for 30 minutes.3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propyl4-methylbenzenesulfonate (501 mg, 1.34 mmol) was added, and theresulting reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was quenched with water (30 ml) at 0° C. andextracted with ethyl acetate (60 ml×2). The combined organic layers werewashed with brine (30 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a residue which was purifiedby silica gel flash chromatography (eluted with 30% ethyl acetate inhexane) to afford 2-(3-(3-((1r,3r)-3-(benzyloxy)cyclobutoxy)propoxy)propoxy)tetrahydro-2H-pyran (234 g,yield 47%) as colorless oil.

Step 5: (1r, 3r)-3-(3-(3-hydroxypropoxy)propoxy)cyclobutanol

A mixture of 2-(3-(3-((1r,3r)-3-(benzyloxy)cyclobutoxy)propoxy)propoxy)tetrahydro-2H-pyran (468 g,1.23 mmol), palladium on carbon (10%, 60 mg) in methanol (30 ml) wasstirred at room temperature overnight under hydrogen atmosphere(hydrogen balloon). Palladium on carbon was removed through filtrationand washed with methanol (5 ml×2). The combined filtrates wereconcentrated under reduced pressure to afford (1r,3r)-3-(3-(3-hydroxypropoxy)propoxy)cyclobutanol (240 mg, yield: 95%) ascolorless oil.

Step 6: 3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propan-1-ol

To a solution of (1r, 3r)-3-(3-(3-hydroxypropoxy)propoxy)cyclobutanol(100 mg, 0.49 mmol) in N,N-dimethylformamide (3 ml) was added sodiumhydride (60% in mineral oil) (28 mg, 0.69 mmol) at 0° C., and theresulting mixture was stirred at room temperature for 30 minutes.7-(6-fluoropyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (96 mg, 0.35mmol) was added, and the resulting reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was quenched with water(30 ml) at 0° C. and extracted with ethyl acetate (60 ml×2). Thecombined organic layers were washed with brine (30 ml), dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive a residue which was purified by silica gel flash chromatography(eluted with 5% methanol in dichloromethane) to afford 3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propan-1-ol(75 mg, yield 34%) as white solid.

Step 7: 3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propanal

To a stirred solution of 3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propan-1-ol(70 mg, 0.15 mmol) in dichloromethane (5 ml) was added Dess-Martinperiodinane (129 mg, 0.3 mmol) at 0° C. The resulting reaction mixturewas allowed to warm up to room temperature and stirred at thistemperature for additional 30 minutes. The reaction mixture was quenchedwith aqueous solution of sodium bicarbonate (10 ml) and extracted withdichloromethane (20 ml×2), washed with brine (20 ml), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford crude 3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propanal(80 mg, crude) as white solid which was used in next step withoutfurther purification.

Step 8: 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione

A mixture of5-(azetidin-3-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (70 mg, 0.17 mmol) [prepared as shown in scheme belowusing procedures described above and common procedures known to thoseskilled in the art], N-ethyl-N-isopropylpropan-2-amine (44 mg, 0.35mmol), acetic acid (1 drop) and 3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propanal(80 mg, 0.17 mmol) in methanol (5 ml) was stirred at room temperaturefor 30 min, followed by addition of sodium cyonobrohydriole (22 mg, 0.35mmol) at room temperature. The resulting mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was quenched withaqueous solution of sodium bicarbonate (sat. 10 ml) and extracted withethyl acetate (20 ml), washed with brine (10 ml), dried over anhydroussodium sulfate, and concentrated under reduced pressure to afford acrude residue which was purified by prep. TLC (eluted with 10% methanolin dichloromethane) to afford2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)isoindoline-1,3-dione(20 mg, yield: 15%) as white solid.

Compound 99: 1H NMR (400 Hz, DMSO-d6): δ 1.40-1.56 (m, 2H), 1.62-1.75(m, 2H), 1.83-2.09 (m, 2H), 2.34-2.50 (m, 3H), 2.58-2.73 (m, 2H),2.83-2.93 (m, 1H), 3.01-3.13 (m, 2H), 3.37-3.52 (m, 8H), 3.77 (s, 2H),3.95 (s, 3H), 4.18 (s, 1H), 5.02-5.13 (m, 2H), 5.29-5.37 (m, 1H), 6.94(d, J=8.0 Hz, 1H), 7.21-7.29 (m, 2H), 7.59-7.65 (m, 2H), 7.80 (d, J=7.2Hz, 1H), 7.97 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.31 (d, J=7.6 Hz, 1H),8.50 (d, J=5.2 Hz, 1H), 8.63 (s, 1H), 9.35 (s, 1H), 11.11 (s, 1H).(M+H)⁺ 773.5.

Synthetic Scheme for Exemplary Compound 100

2-(2,6-dioxopiperidin-3-yl)-5-(6-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)butoxy)butoxy)-2-azaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 100: ¹H NMR (400 MHz, CDCl₃): δ 1.65-1.67 (m, 6H), 1.74-1.81(m, 2H), 1.87-1.94 (m, 2H), 2.00-2.06 (m, 1H), 2.09-2.14 (m, 1H),2.18-2.24 (m, 2H), 2.54-2.59 (m, 2H), 2.68-2.90 (m, 3H), 3.37-3.53 (m,5H), 3.91 (t, J=7.6 Hz, 3H), 3.98 (d, J=8.0 Hz, 3H), 4.39 (t, J=6.4 Hz,2H), 4.90-4.94 (m, 1H), 6.45 (d, J=1.6 Hz, 1H), 6.72 (d, J=1.6 Hz, 1H),6.85 (d, J=8.4 Hz, 1H), 7.35 (d, J=6 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H),7.56 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 8.05 (s,1H), 8.21 (d, J=8.0 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.60 (d, J=5.6 Hz,1H), 9.34 (s, 1H). (M+H)⁺ 771.6.

Synthetic Scheme of Exemplary Compound 101

5-((1-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propyl)azetidin-3-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 101: 1H NMR (400 Hz, D6-DMSO): δ 1.56-1.59 (m, 2H), 1.71-1.77(m, 2H), 1.95-2.05 (m, 2H), 2.34-2.46 (m, 3H), 2.50-2.67 (m, 3H),2.83-2.93 (m, 1H), 3.32-3.49 (m, 9H), 3.88-3.92 (m, 1H), 4.17-4.20 (m,1H), 4.55 (t, J=5.6 Hz, 1H), 5.05-5.13 (m, 2H), 5.46-5.49 (m, 1H),7.25-7.28 (m, 2H), 7.52 (d, J=5.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.82(d, J=8.0 Hz, 1H), 7.87 (s, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.39 (s, 1H),8.45 (d, J=6.0 Hz, 1H), 8.83 (s, 1H), 9.39 (s, 1H), 11.11 (s, 1H), 11.86(s, 1H). (M+H)⁺ 827.5.

Using analogous procedures the following were prepared: Compound 105.

Synthetic Scheme for Exemplary Compound 103

5-((14-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1:5-bromo-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine

To a solution of compound 5-bromo-2-fluoropyridine (2.0 g, 9.5 mmol) inDMF (20 mL) was added 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol (2.6g, 7.91 mmol) and NaH (950 mg, 24 mmol, 60%) at 0° C. The resultingmixture was stirred at 20° C. for 18 hours. TLC (PE:EA=1:1, Rf=0.5)showed 5-bromo-2-fluoropyridine was consumed. The mixture was dilutedwith EA (30 mL), washed with water (3*30 mL) and brine (30 mL). Theorganic layer was dried and concentrated to give crude product, whichwas purified by column chromatography on silica gel with PE:EA (1:1) togive the desired product (3.6 g) as a colorless oil.

Step 2:2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of5-bromo-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy) pyridine(3.6 g, 7.22 mmol) in dioxane (50 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (3.7 g,14.45 mmol), Pd(dppf)Cl₂ (530 mg) and AcOK (1.42 g, 14.45 mmol). Theresulting solution was stirred at 90° C. for 18 hours. The mixture wasfiltered and concentrated. The crude was purified by columnchromatography on silica gel with PE:EA (1:1) to afford the desiredproduct (3.0 g, yield=78%) as a yellow oil.

Step 3:5-(4-bromo-2,3-difluorophenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine

To a solution of 2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.8 g,5.27 mmol) in dioxane/H₂O (55 mL, 10/1, v/v) was added1,4-dibromo-2,3-difluorobenzene (1.72 g, 6.32 mmol, CsF (1.6 g, 10.54mmol) and Pd(PPh₃) (300 mg). The resulting solution was stirred at 90°C. for 18 hours under N2. After the reaction was over, the mixture wasquenched with EA and extracted with EA. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crude waspurified by column chromatography on silica gel with PE:EA (1:1) toafford the desired product (1.5 g, yield=48%) as a brown oil.

Step 4:5-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine

To a solution of5-(4-bromo-2,3-difluorophenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine (1.0 g, 1.68 mmol) in dioxane (20 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (640 mg,2.52 mmol), Pd(dppf)Cl₂ (120 mg) and AcOK (330 mg, 3.36 mmol). Theresulting solution was stirred at 90° C. for 18 hours. LCMS showed5-(4-bromo-2,3-difluorophenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine was consumed completely. The mixture was filtered andconcentrated. The crude was purified by column chromatography on silicagel with PE:EA (3:2) to afford the desired product the desired product(660 mg, yield=95%) as a brown oil.

Step 5:5-(2,3-difluoro-4-(4-nitropyridin-3-yl)phenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridine

To a solution of5-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine(350 mg, 0.544 mmol) in dioxane/H₂O (11 mL, 10/1, v/v) was added3-bromo-4-nitropyridine (121 mg, 0.6 mmol), Na₂CO₃ (120 mg, 1.1 mmol)and Pd(PPh₃)₄ (63 mg). The mixture was stirred at 110° C. for 1 h underN2. After the reaction, the mixture was extracted with ethyl acetate (20mL) and washed with brine (30 mL). The organic solution was dried overanhydrous sodium sulfate and concentrated. The crude was purified bycolumn chromatography on silica gel with PE/EA (1:3) to give the desiredproduct (170 mg) as a yellow oil.

Step 6:8,9-difluoro-7-(6-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

A solution of5-(2,3-difluoro-4-(4-nitropyridin-3-yl)phenyl)-2-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy) pyridine (340 mg, 0.53 mmol) in P(Oet)₃ (3 mL) was stirred at 110°C. for 3 h. After the reaction, the mixture was purified by columnchromatography on silica gel with DCM/MeOH (30:1) to give the desiredproduct (205 mg) as a brown solid.

8,9-difluoro-7-(6-((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl)oxy)pyridin-3-yl)-5H-pyrido[4,3-b]indole

was converted into the final compounds,5-((14-((5-(8,9-difluoro-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound 103) and5-((14-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Compound 112), according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 103: ¹H NMR (400 MHz, CD₃OD): δ 9.46 (s, 1H), 8.63 (d, J=6.8Hz, 1H), 8.38 (s, 1H), 8.00 (d, J=6.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H),7.67 (d, J=8.4 Hz, 1H), 7.61 (d, J=4.8 Hz, 1H), 7.29 (s, 1H), 7.23 (d,J=8.4 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 5.05 (m, 1H), 4.54-4.45 (m, 2H),4.26-4.19 (m, 2H), 3.86 (m, 4H), 370-3.65 (m, 12H), 2.86-2.62 (m, 3H),2.10-2.04 (m, 1H). (M+H)⁺ 774.5.

Compound 112: ¹HNMR (400 MHz, CDCl₃): δ: 11.09 (s, 1H), 9.25 (s, 1H),8.50 (s, 1H), 8.59 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz,1H), 7.69-7.73 (m, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.34 (d,J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.08-5.13 (m, 1H), 4.46 (d, J=4.4Hz, 2H), 4.30-4.34 (m, 2H), 3.95 (s, 3H), 3.79 (s, 4H), 3.60 (s, 4H),3.56 (s, 4H), 3.53 (s, 4H), 2.85-2.88 (m, 1H), 2.61 (s, 2H). (M+H)⁺788.5.

Synthetic Scheme for Exemplary Compound 104

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 104: ¹H NMR (400 MHz, DMSO-d6): δ 1.73-1.79 (m, 4H), 1.97-1.99(m, 2H), 2.31-2.37 (m, 2H), 2.40-2.49 (m, 2H), 2.54-2.59 (m, 1H),2.83-2.88 (m, 1H), 3.38 (t, J=6.4 Hz, 2H), 3.43-3.49 (m, 6H), 3.82-3.85(m, 2H), 3.75 (s, 3H), 4.16-4.18 (m, 1H), 4.20-4.26 (m, 2H), 4.43-4.47(m, 1H), 5.02-5.07 (m, 1H), 5.31-5.34 (m, 1H), 6.62-6.64 (m, 1H),6.78-6.79 (m, 1H), 6.93 (t, J=8.4 Hz, 1H), 7.59-6.72 (m, 3H), 7.96 (s,1H), 8.17-8.19 (m, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.49 (d, J=6.4 Hz, 1H),8.62-8.63 (m, 1H), 9.35 (s, 1H), 11.06 (s, 1H). (M+H)⁺ 773.5.

Using procedures analogous to those described above the followingcompounds were prepared: 125 (while also using procedures described inCompound 67), 148 (while also using procedures described in Compound67), Compound 170.

Synthetic Scheme for Exemplary Compound 106

Prepared according to the synthetic schemes below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 106: ¹H NMR (400 MHz, DMSO-d6): δ 1.54-1.68 (m, 10H), 1.84-1.88(m, 2H), 2.12-2.14 (m, 1H), 2.77-2.93 (m, 5H), 3.40-3.45 (m, 4H),3.64-3.75 (m, 4H), 3.91 (s, 3H), 4.09 (t, J=6.4 Hz, 2H), 4.39-4.46 (m,1H), 4.89-4.99 (m, 1H), 5.41-5.50 (m, 1H), 6.90 (d, J=8.4 Hz, 1H),7.14-7.2 (m, 1H), 7.32-7.35 (m, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.55 (s,1H), 7.76 (d, J=8.0 Hz, 1H), 7.92-8.00 (m, 1H), 8.21 (d, J=8.0 Hz, 1H),8.43 (d, J=2.0 Hz, 1H), 8.59 (d, J=5.6 Hz, 1H), 9.33 (s, 1H). (M+H)⁺759.6.

Synthetic Scheme for Exemplary Compound 107

2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)butoxy)butoxy)isoindoline-1,3-dione

Prepared according to the synthetic schemes below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 107: 1HNMR (400 MHz, CDCl₃): δ 1.61-1.65 (m, 2H), 1.72-1.77 (m,4H), 1.90-1.93 (m, 2H), 1.99-2.04 (m, 1H), 2.14-2.22 (m, 3H), 2.44-2.49(m, 2H), 2.78-3.01 (m, 6H), 3.44-3.49 (m, 4H), 3.92 (s, 3H), 3.99-4.05(m, 2H), 4.14 (t, J=6.2 Hz, 2H), 4.94-4.98 (m, 1H), 5.17-5.20 (m, 1H),6.81 (d, J=8.4 Hz, 1H), 7.19-7.21 (m, 1H), 7.33-7.37 (m, 2H), 7.49 (d,J=8.4 Hz, 1H), 7.56 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.90-7.93 (m, 1H),8.21 (d, J=8.4 Hz, 1H), 8.35 (br, 1H), 8.45-8.46 (m, 1H), 8.59 (d, J=5.6Hz, 1H), 9.34 (s, 1H). (M+H)⁺ 771.6.

Synthetic Scheme for Exemplary Compound 108

2-(2,6-dioxopiperidin-3-yl)-5-((6-((6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 108: ¹H NMR (400 MHz, DMSOd-6): δ 1.43-1.44 (m, 4H), 1.70-1.74(m, 4H), 1.98-2.04 (m, 1H), 2.44-2.47 (m, 1H), 2.56-2.60 (m, 1H), 2.65(t, J=6.0 Hz, 4H), 2.83-2.92 (m, 1H), 3.95 (s, 3H), 4.10 (t, J=6.0 Hz,2H), 4.22 (t, J=6.4 Hz, 2H), 5.07-5.11 (m, 1H), 5.30-5.35 (m, 1H),5.39-5.45 (m, 1H), 6.34-6.37 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 7.24-7.26(m, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.59-7.65 (m, 3H), 7.72 (d, J=8.0 Hz,1H), 7.97 (s, 1H), 8.17-8.21 (m, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.50 (d,J=6.0 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H), 9.36 (s, 1H), 11.10 (s, 1H).(M+H)⁺ 795.5.

Synthetic Scheme for Exemplary Compound 109

2-(2,6-dioxopiperidin-3-yl)-5-((6-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)oxy)hexyl)oxy)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 109: ¹H NMR (400 MHz, DMSOd-6): δ 1.47 (s, 4H), 1.72-1.78 (m,4H), 2.02-2.05 (m, 2H), 2.33 (s, 1H), 2.63-2.66 (m, 4H), 2.88-2.89 (m,1H), 3.41-3.49 (m, 2H), 3.96 (s, 2H), 4.18-4.23 (m, 3H), 5.04-5.12 (m,2H), 5.42 (br, 1H), 6.19 (s, 1H), 6.55-6.56 (m, 1H), 6.98 (d, J=8.4 Hz,1H), 7.34 (d, J=7.2 Hz, 1H), 7.41 (s, 1H), 6.63 (s, 2H), 7.81-7.83 (m,1H), 7.95-7.97 (m, 2H), 8.21 (d, J=8.4 Hz, 1H), 8.32 (d, J=7.2 Hz, 1H),8.50 (d, J=4.0 Hz, 1H), 8.64 (s, 1H), 9.36 (s, 1H), 11.11 (s, 1H).(M+H)⁺ 795.5.

Synthetic Scheme for Exemplary Compound 111

2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione

Step 1: tert-butyl 3-(prop-2-yn-1-yloxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate(1.0 g, 12.2 mmol) in N,N-dimethylformamide (10 ml) was added sodiumhydride (60% in mineral oil) (255 mg, 6.36 mmol) at 0° C., and theresulting mixture was stirred at 0° C. for 30 minutes. The reactionmixture was allowed to warm up to room temperature and stirred foradditional 30 min, then 3-bromoprop-1-yne (818 mg, 6.94 mmol) was added,and the resulting reaction mixture was stirred at 50° C. overnight. LCMSshowed the reaction was complete. The reaction mixture was quenched withwater (10 ml) at 0° C. and extracted with ethyl acetate (30 ml×2). Thecombined organic layers were washed with brine (30 ml×2), dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive a residue which was purified by silica gel flash chromatography(eluted with 10% ethyl acetate in hexane) to afford tert-butyl3-(prop-2-yn-1-yloxy)azetidine-1-carboxylate (1.03 g, yield 84%) ascolorless oil.

Step 2: tert-butyl3-((3-(5-hydroxypyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate

To a stirred solution of tert-butyl3-(prop-2-yn-1-yloxy)azetidine-1-carboxylate (900 mg, 4.27 mmol) and6-bromopyridin-3-ol (734 mg, 4.27 mmol) in acetonitrile (10 ml) wasadded triethylamine (863 mg, 8.54 mmol) followed bybis(triphenylphosphine)palladium(II) chloride (150 mg, 0.214 mmol) andcuprous iodide (41 mg, 0.214 mmol) at room temperature under nitrogenatmosphere; the mixture was degassed with nitrogen three times. Thereaction mixture was allowed to warm up to 65° C. and stirred overnight.TLC showed the reaction was complete. The mixture was partitionedbetween ethyl acetate (100 ml) and water (50 ml). The organic layer waswashed with brine (50 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give crude residue which waspurified by silica gel flash column chromatography (eluted with 100%ethyl acetate in hexane) to afford tert-butyl3-((3-(5-hydroxypyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate(550 mg, yield 42%) as brown oil.

Step 3: tert-butyl 3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate

A solution of tert-butyl3-((3-(5-hydroxypyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate(100 mg, 0.325 mmol), (1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutylmethanesulfonate (137 mg, 0.325 mmol) and cesium carbonate (211 mg, 0.65mmol) in dry N,N-dimethylformamide (2 ml) was stirred at 70° C. for 36hours. TLC showed the reaction was complete. The mixture was partitionedbetween ethyl acetate (50 ml) and water (25 ml). The organic layer wascollected, washed with brine (25 ml), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give crude residuewhich was purified by silica gel flash column chromatography (elutedwith 3% methanol in dichloromethane) to afford tert-butyl 3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylate(60 mg, yield 29%) as white solid.

Tert-butyl 3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidine-1-carboxylatewas converted into the final compound,2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione,according to the synthetic scheme below using procedures described aboveand common procedures known to those skilled in the art.

Compound 111: ¹HNMR (400 MHz, DMSO-d6): δ 1.98-2.02 (m, 1H), 2.54-2.73(m, 6H), 2.83-2.92 (m, 1H), 3.95-3.97 (m, 5H), 4.31-4.34 (m, 2H), 4.50(s, 2H), 4.67-4.72 (m, 1H), 5.04-5.13 (m, 2H), 5.42-5.48 (m, 1H),6.67-6.69 (m, 1H), 6.82 (s, 1H), 6.69-7.01 (m, 1H), 7.33-7.36 (m, 1H),7.53-7.55 (m, 1H), 7.63-7.67 (m, 3H), 8.01 (s, 1H), 8.21-8.26 (m, 2H),8.33-8.37 (m, 1H), 8.51-8.55 (m, 1H), 8.65-8.66 (m, 1H), 9.39 (s, 1H),11.07 (s, 1H). (M+H)⁺ 788.5.

Using analogous procedures the following exemplary compounds wereprepared: 194.

Synthetic Scheme for Exemplary Compound 114

2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)butoxy)pentyl)oxy)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 114: ¹H NMR (400 MHz, CDCl₃): δ 1.52-1.59 (m, 2H), 1.63-1.67(m, 5H), 1.83-1.90 (m, 1H), 2.11-2.16 (m, 2H), 2.43-2.54 (m, 4H),2.71-2.92 (m, 4H), 3.39-3.49 (m, 6H), 3.95 (s, 3H), 4.08 (t, J=6.4 Hz,2H), 4.23-4.29 (m, 1H), 4.94 (dd, J=5.2, 12.0 Hz, 1H), 6.83 (d, J=8.4Hz, 1H), 7.17 (dd, J=2.0, 8.0 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.44 (d,J=6.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.75 (d, J=8.4 Hz,1H), 7.91 (dd, J=2.4, 8.8 Hz, 1H), 8.14 (m, 1H), 8.21 (d, J=8.0 Hz, 1H),8.48 (d, J=2.4 Hz, 1H), 8.58 (d, J=5.2 Hz, 1H), 9.34 (s, 1H). (M+H)⁺760.5.

Using procedures analogous to those for Compound 140, the following wereprepared: Compound 115.

Synthetic Scheme for Exemplary Compound 116

2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)butoxy)butyl)-2-azaspiro[3.3]heptan-6-yl)oxy)isoindoline-1,3-dione

Prepared according to the synthetic schemes below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 116: 1HNMR (400 MHz, CDCl₃): δ 1.39-1.42 (m, 2H), 1.47-1.52 (m,2H), 1.64-1.70 (m, 2H), 1.77-1.82 (m, 2H), 2.01-2.07 (m, 1H), 2.21-2.26(m, 2H), 2.54-2.64 (m, 3H), 2.75-2.90 (m, 5H), 3.42-3.45 (m, 3H),3.61-3.71 (m, 4H), 3.95 (s, 3H), 4.35 (t, J=6.2 Hz, 2H), 4.78-4.82 (m,1H), 5.09-5.13 (m, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.20-7.25 (m, 2H),7.60-7.63 (m, 2H), 7.79 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 8.18-8.20 (m,1H), 8.31 (d, J=8.0 Hz, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.65 (s, 1H), 9.34(s, 1H), 11.11 (s, 1H). (M+H)⁺ 771.6.

Synthetic Scheme for Compound 118

2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic schemes below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 118: ¹H NMR (400 MHz, DMSO-d6): δ 1.98-2.03 (m, 1H), 2.09-2.15(m, 1H), 2.20-2.24 (m, 1H), 2.70-2.87 (m, 5H), 4.01-4.04 (m, 4H),4.29-4.34 (m, 1H), 4.46 (s, 2H), 4.75-4.79 (m, 1H), 4.89-4.95 (m, 1H),5.00-5.06 (m, 1H), 5.33-5.40 (m, 2H), 5.65-5.70 (m, 1H), 6.53-6.55 (m,1H), 6.79 (s, 1H), 7.08-7.11 (m, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.56-7.65(m, 4H), 7.95 (s, 1H), 8.19-8.30 (m, 3H), 8.60-8.64 (m, 2H), 9.38 (s,1H). (M+H)⁺ 856.5.

Synthetic Scheme for Exemplary Compound 121

(2S,4R)-1-((S)-20-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Step 1: 14-((5-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol

To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (20 g, 83.93mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (60% inmineral oil) (1.36 g, 34.09 mmol) at 0° C., and the resulting mixturewas stirred at 0° C. for 30 minutes. Then 5-bromo-2-fluoropyridine (5 g,28.41 mmol) was added, and the resulting reaction mixture was stirred at50° C. for 2 hour. TLC showed the reaction was complete. The reactionmixture was quenched with water (150 ml) at 0° C. and extracted withethyl acetate (150 ml×2). The combined organic layers was washed withbrine (200 ml×2), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to afford a crude residue which was purified bysilica gel flash chromatography (eluted with 2% methanol indichloromethane) to afford14-((5-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (8 g,yield 72%) as colorless oil.

Step 2: tert-butyl17-((5-bromopyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecan-1-oate

To a stirred solution of14-((5-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (2.00 g,5.07 mmol) and tetrabutyl ammonium chloride (1.41 g, 5.07 mmol) indichloromethane (20 ml) and sodium hydroxide (20 ml, 35% in water) wasadded tert-butyl 2-bromoacetate (2.97 g, 15.22 mmol) at 0° C. Thereaction mixture was then allowed to warm up to room temperature andstirred at room temperature overnight. The organic layer was collected,the aqueous layer was extracted with dichloromethane (20 ml). Thecombined organic layers were washed with brine (20 ml), dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive a crude residue which was purified by silica gel flash columnchromatography (eluted with 50% ethyl acetate in hexane) to affordtert-butyl17-((5-bromopyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecan-1-oate(1.64 g, yield 64%) as colorless oil.

Step 3: tert-butyl17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecan-1-oate

To a stirred solution of 7-bromo-5H-pyrido[4,3-b]indole (300 mg, 1.22mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (620mg, 2.44 mmol), and potassium acetate (239 mg, 2.44 mmol) in dioxane (5ml) was added 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II)dichloride (176 mg, 0.24 mmol) at room temperature undernitrogen atmosphere, the mixture was degassed with nitrogen three times.The result mixture was stirred at 90° C. overnight. LCMS showed thereaction was complete. To the reaction mixture were added14-((5-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (930 mg,1.83 mmol), aqueous sodium carbonate solution (2N, 3.2 ml) andtetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol); the mixturewas degassed with nitrogen three times. The resulting mixture wasstirred at 80° C. for 3 hours under nitrogen atmosphere. The reactionmixture was partitioned between ethyl acetate (30 ml) and water (20 ml).The organic layer was collected and the aqueous layer was extracted withethyl acetate (20 ml). The combined organic layers were washed withbrine (30 ml), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a crude residue which was purified bysilica gel flash chromatography (eluted with 2% methanol indichloromethane) to afford tert-butyl17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecan-1-oate(260 mg, yield 36%) as grey oil.

Step 4:17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecan-1-oicacid

A mixture of tert-butyl17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecan-1-oate(130 mg, 0.22 mmol) and 2,2,2-trifluoroacetic acid (2 ml) indichloromethane (1 ml) was stirred at room temperature for one hours.The volatiles were evaporated under reduced pressure to give17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecan-1-oicacid (120 mg, crude) as brown solid which was used in next step directlywithout further purification.

Step 5:(2S,4R)-1-((S)-20-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaicosan-1-oyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

To a stirred solution of17-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecan-1-oicacid (120 mg, crude),(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (105 mg, 0.22 mmol), and N-ethyl-N-isopropylpropan-2-amine(142 mg, 1.10 mmol) in anhydrous N,N-dimethylformamide (3 ml) was addedHATU (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (167 mg, 0.44 mmol) at room temperature and stirredfor 20 minutes. The mixture was partitioned between ethyl acetate (20ml) and water (20 ml). The organic layer was collected, washed withbrine (20 ml×2), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a crude residue which was purified bypreparative TLC (eluted with 10% methanol in dichloromethane) to afford(2S,4R)-1-((S)-20-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaicosan-1-oyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(28 mg, yield 13%) as white solid.

¹H NMR (400 MHz, DMSOd-6): δ 0.93 (s, 9H), 1.36-1.47 (m, 3H), 1.73-1.80(m, 1H), 1.96-2.09 (m, 2H), 3.23-3.60 (m, 16H), 3.79 (t, J=3.6 Hz, 2H),3.96 (s, 2H), 4.28 (s, 1H), 4.42-4.46 (m, 3H), 4.54 (d, J=9.6 Hz, 1H),4.90 (t, J=7.6 Hz, 1H), 5.12 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 7.35-7.43(m, 5H), 7.65-7.69 (m, 2H), 7.87 (s, 1H), 8.12-8.15 (m, 1H), 8.37-8.43(m, 2H), 8.51 (d, J=5.6 Hz, 1H), 8.59 (d, J=1.6 Hz, 1H), 8.97 (s, 1H),9.51 (s, 1H), 12.28 (s, 1H). (M+H)⁺ 966.7.

Using analogous procedures the following were prepared: Compound 1,Compound 5, Compound 6, Compound 120, and Compound 122.

Synthetic Scheme for Exemplary Compound 119

(2S,4R)-1-((S)-17-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 119: ¹H NMR (400 MHz, DMSO-d₆): δ 0.93 (s, 9H), 1.35 (t, J=6.8Hz, 3H), 1.77-1.78 (s, 1H), 2.02-2.04 (m, 1H), 2.44 (s, 3H), 3.53-3.64(m, 14H), 3.80-3.85 (m, 2H), 3.95 (s, 2H), 4.28 (s, 1H), 4.44 (d, J=8.2Hz, 1H), 4.54 (d, J=9.6 Hz, 1H), 4.58-4.63 (m, 2H), 4.90 (s, 1H), 5.12(s, 1H), 7.26-7.50 (m, 5H), 7.54 (d, J=5.8 Hz, 1H), 7.66 (d, J=8.2 Hz,1H), 7.90 (s, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.42-8.45 (m, 3H), 8.85 (s,1H), 8.97 (s, 1H), 9.41 (s, 1H), 11.92 (s, 1H). (M+H)⁺ 990.7.

Synthetic Scheme for Exemplary Compound 126

2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)pentyl)oxy)isoindoline-1,3-dione

Step 1: (1r, 3r)-3-(methylamino)cyclobutanol

To a solution of tert-butyl ((1r, 3r)-3-hydroxycyclobutyl)carbamate (2g, 10.7 mmol) in tetrahydrofuran (30 ml) was added lithium aluminumhydride (1.6 g, 42.7 mmol) at 0° C. The mixture was stirred at 65° C.for 2 hours. TLC showed the reaction was complete. The mixture wasquenched with water (1.6 ml), sodium hydroxide (1.6 ml, 15% in water)and water (4.8 ml) at 0° C. The mixture was stirred at room temperaturefor 15 minutes and filtered. The filtrate was dried over anhydroussodium sulfate, and concentrated under reduced pressure to give a crude(1r, 3r)-3-(methylamino)cyclobutanol (1.3 g) as colorless oil which wasused in the next step without further purification.

Step 2: tert-butyl ((1r, 3r)-3-hydroxycyclobutyl)(methyl)carbamate

To a solution of (1r, 3r)-3-(methylamino)cyclobutanol (1.3 g, 12.8 mmol)and triethylamine (2.6 g, 25.7 mmol) in dichloromethane (10 ml) wasadded di-tert-butyl carbonate (4.2 g, 19.28 mmol) at room temperature.The mixture was stirred at room temperature for 12 hours. TLC showed thereaction was complete. The mixture was diluted with dichloromethane (10ml) and washed with aqueous hydrochloride acid (1N, 10 ml). The organiclayer was collected, washed with brine (20 ml), dried over anhydroussodium sulfate, and concentrated under reduced pressure to give a cruderesidue which was purified by silica gel flash chromatography (elutedwith 33-50% ethyl acetate in hexane) to afford tert-butyl ((1r,3r)-3-hydroxycyclobutyl)(methyl)carbamate (1.2 g, two steps 56%) ascolorless oil.

Step 3: tert-butyl methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate

To a solution of7-(6-fluoropyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (300 mg, 1.1mmol) and tert-butyl ((1r, 3r)-3-hydroxycyclobutyl)(methyl)carbamate(218 mg, 1.1 mmol) in 1-methylpyrrolidin-2-one (3 ml) was added sodiumhydride (60% in mineral oil) at 0° C. The mixture was allowed to cool toroom temperature and stirred at room temperature for 30 minutes. LC-MSshowed the reaction was complete. The mixture was partitioned betweenethyl acetate (30 ml) and water (30 ml). The organic layer wascollected, washed with brine (20 ml), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give a crude residuewhich was purified by silica gel flash chromatography (eluted with 1-2%methanol in dichloromethane) to afford tert-butyl methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate(450 mg, 91%) as light yellow oil.

Step 4: afford tert-butyl 6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

A mixture of tert-butyl methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate(450 mg, 0.98 mmol) and 2,2,2-trifluoroacetic acid (2 ml) indichloromethane (2 ml) was stirred at room temperature for 1 hour. TLCshowed the reaction was complete. The volatiles were evaporated underreduced pressure. The residue was taken up in methanol (5 ml), followedby sequential addition of N-ethyl-N-isopropylpropan-2-amine (380 mg,2.94 mmol), tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (207mg, 0.98 mmol) and acetic acid (71 mg, 1.18 mmol) at 0° C. The resultingmixture was stirred at room temperature for 30 minutes and sodiumcyanoborohydride (124 mg, 1.96 mmol) was added. The mixture was stirredat room temperature for 18 hours. TLC showed the reaction was complete.The mixture was concentrated and the residue was partitioned betweenethyl acetate (20 ml) and water (20 ml). The organic layer wascollected, washed with brine (20 ml), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give a crude residuewhich was purified by silica gel flash chromatography (eluted with 2-5%methanol in dichloromethane) to afford tert-butyl 6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate(240 mg, two steps 44%) as white solid.

Step 5: N-methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)-2-azaspiro[3.3]heptan-6-amine

A mixture of tert-butyl 6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate(100 mg, 0.18 mmol) and 2,2,2-trifluoroacetic acid (0.5 ml) in anhydrousdichloromethane (0.5 ml) was stirred at room temperature for 1 hour. TLCshowed the reaction was complete. The mixture was concentrated underreduced pressure to give crude N-methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)-2-azaspiro[3.3]heptan-6-amine(100 mg) which was used in the next step without further purification.

Step 6: 2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)pentyl)oxy)isoindoline-1,3-dione

N-methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)-2-azaspiro[3.3]heptan-6-amine(100 mg, crude) and N-ethyl-N-isopropylpropan-2-amine (70 mg, 0.54 mmol)in methanol (10 ml) was added5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanal(65 mg, 0.18 mmol) and acetic acid (13 mg, 0.21 mmol) at 0° C. Themixture was stirred at room temperature for 30 minutes and then sodiumcyanoborohydride (23 mg, 0.36 mmol) was added. The mixture was stirredat room temperature for 16 hours. TLC showed the reaction was complete.The mixture was concentrated under reduced pressure to give a cruderesidue which was purified by HPLC to afford2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)pentyl)oxy)isoindoline-1,3-dione(57.3 mg, two steps 40%) as white solid.

¹H NMR (400 MHz, DMSO-d6): δ 1.42-1.51 (m, 4H), 1.75-1.79 (m, 2H),2.03-2.06 (m, 1H), 2.54 (s, 3H), 2.58-2.68 (m, 5H), 2.81-2.94 (m, 2H),3.11-3.17 (m, 2H), 3.61-3.71 (m, 3H), 3.98-4.11 (m, 6H), 4.15 (s, 3H),4.17-4.23 (m, 3H), 5.10-5.14 (m, 1H), 5.25-5.31 (m, 1H), 7.03 (d, J=8.4Hz, 1H), 7.33-7.42 (m, 2H), 7.84-7.89 (m, 1H), 8.22-8.32 (m, 3H), 8.55(d, J=8.0 Hz, 1H), 8.71 (s, 1H), 8.78 (d, J=6.4 Hz, 1H), 9.78 (s, 1H),10.05 (brs, 1H), 10.51 (brs, 1H), 11.11 (s, 1H). (M+H)⁺ 796.6.

Synthetic Scheme for Exemplary Compound 127

3-(5-(4-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Step 1:(1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methanol

To the mixture of7-(6-fluoropyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole (200 mg, 0.72mmol) and piperidin-4-ylmethanol (108 mg, 0.93 mmol) in1-methylpyrrolidin-2-one (5 ml) was added potassium carbonate (298 mg,2.16 mmol), and it was stirred at 100° C. overnight under nitrogenatmosphere. The cooled reaction mixture was partitioned between ethylacetate (30 ml) and water (30 ml). The organic layer was collected,washed with brine (30 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a crude residue which waspurified by silica gel flash chromatography (eluted with 2-5% methanolin dichloromethane) to afford(1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methanol(205 mg, yield 76%) as light yellow solid.

Step 2:1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidine-4-carbaldehyde

To a solution of Dess-Martin periodinane (136 mg, 0.32 mmol) indichloromethane (3 ml)(1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methanol(60 mg, 0.16 mmol) was added and stirred at room temperature for 1 hourunder nitrogen atmosphere. The reaction mixture was partitioned betweendichloromethane (20 ml) and water (20 ml). The organic layer wascollected, washed with brine (20 ml), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give a crude residuewhich was purified by prep TLC (eluted with 3% methanol indichloromethane) to afford1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidine-4-carbaldehyde(58 mg, yield 97%) as white solid.

Step 3: tert-Butyl4-(1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate

To a solution of 5-bromo-3H-isobenzofuran-1-one (45 g, 211.24 mmol, 1.00eq) and tert-butyl piperazine-1-carboxylate (39.34 g, 211.24 mmol, 1.00eq) in dioxane (500 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (19.34 g, 21.12 mmol, 0.10 eq),4,5-bis (diphenylphosphino)-9,9-dimethylxanthene (12.22 g, 21.12 mmol,0.10 eq) and potassium phosphate (89.68 g, 422.48 mmol, 2.00 eq). Themixture was heated to 100° C. for 16 hr under nitrogen protection. Themixture was filtered through a pad of celite and filtrate wasconcentrated in vacuum. The residue was triturated in ethyl acetate:petroleum ether (500 mL, v/v=1:2). Tert-Butyl4-(1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (50 g, 122.5mmol, 58% yield, 78% purity) was obtained as yellow solid.

Step 4: 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)benzoic acid

To a mixture of tert-butyl4-(1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (47.8 g, 150.14mmol, 1.00 eq) in tetrahydrofuran (150 mL), methanol (150 mL) and water(150 mL) was added sodium hydroxide (24 g, 600 mmol, 4.00 eq). Themixture was stirred at 25° C. for 1 hr. The solution was adjusted topH=4-5 with aqueous hydrochloride solution (1M) and extracted with ethylacetate (100 mL×5). The organic layers were concentrated in vacuum. Thecrude was triturated in ethyl acetate: petroleum ether (450 mL,v:v=1:2). 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)benzoic acid (40 g, 118.91 mmol, 79%yield) was obtained as yellow solid.

Step 5: tert-Butyl4-[3-(hydroxymethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate

To a solution of4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)benzoic acid(20 g, 59.46 mmol, 1.00 eq) in methanol (100 mL) and ethyl acetate (100mL) was added TMS-diazomethane (2 M, 89 mL, 3.00 eq) at −10° C. Thesolution was stirred at −10° C. for 0.25 hr. The solution was quenchedwith water (300 mL) and extracted with ethyl acetate (150 mL×3). Theorganic layer was dried over sodium sulfate and filtered. The filtratewas concentrated. Tert-Butyl4-[3-(hydroxymethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate(20.84 g, crude) was obtained as brown oil.

Step 6: tert-Butyl4-[3-(bromomethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[3-(hydroxymethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate(20.84 g, 59.47 mmol, 1.00 eq) in tetrahydrofuran (200 mL) was addedtriphenylphosphine (23.4 g, 89.21 mmol, 1.50 eq) and tetrabromomethane(29.58 g, 89.21 mmol, 1.50 eq). The solution was stirred at 25° C. for 1hr. The solution was quenched with water (200 mL) and extracted withethyl acetate (100 mL×2). The organic layer was dried over sodiumsulfate and filtered. The filtrate was concentrated in vacuum. Theresidue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:50-1:8). Tert-Butyl4-[3-(bromomethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate (12g, 29.03 mmol, 49% yield) was obtained as a pale-yellow oil.

Step 7: tert-Butyl4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[3-(bromomethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate (12g, 29.03 mmol, 1.00 eq) in acetonitrile (300 mL) was added3-aminopiperidine-2,6-dione; hydrochloride (7.17 g, 43.55 mmol, 1.50 eq)and N-ethyl-N-isopropylpropan-2-amine (11.26 g, 87.09 mmol, 15 mL, 3.00eq). The solution was stirred at 80° C. for 16 hr. LCMS showed reactionwas almost complete. The reaction mixture was cooled to 20° C. andfiltered. The solid was washed with acetonitrile (30 mL). tert-Butyl4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate(6 g, 14 mmol, 48% yield) was obtained as a white solid.

Step 8: 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl) piperidine-2,6-dione

To a mixture of tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate(6 g, 14 mmol, 1.00 eq) in dioxane (70 mL) was addedhydrochloride/dioxane (4 M, 100 mL, 28.57 eq). The mixture was stirredat 25° C. for 2 hr. The mixture was poured into ethyl acetate (400 mL)and stirred for 30 minutes. The suspension was filtered and solid wascollected. 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (5 g, 13.71 mmol, 98% yield, hydrochloric salt) wasobtained as a white solid.

Step 9:3-(5-(4-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidine-4-carbaldehyde(58 mg, 0.15 mmol), N-ethyl-N-isopropylpropan-2-amine (32 mg, 0.23mmol), 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione(51 mg, 0.15 mmol) and acetic acid (0.5 ml) in methanol (4 ml) wasstirred at room temperature for 30 minutes. It was followed by theaddition of sodium cyanoborohydride (21 mg, 2.10 mmol) and stirring for1 hour at room temperature. The mixture was partitioned between ethylacetate (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate,and concentrated under reduced pressure to give a crude residue whichwas purified by prep TLC (eluted with 10% methanol in dichloromethane)to afford3-(5-(4-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(57 mg, yield 53%) as light yellow solid.

¹H NMR (400 MHz, DMSO-d6): δ 1.11-1.23 (m, 4H), 1.82-1.99 (m, 4H),2.30-2.39 (m, 3H), 2.60 (br, 4H), 2.86-2.94 (m, 3H), 3.17 (s, 2H), 3.98(s, 3H), 4.10 (br, 1H), 4.21 (d, J=16.8 Hz, 1H), 4.32-4.41 (m, 3H), 5.05(dd, J=13.2 Hz, 1H), 6.96 (d, J=9.2 Hz, 1H), 706-7.08 (m, 2H), 7.53 (d,J=8.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.69 (d, J=6.0 Hz, 1H), 7.95 (s,1H), 8.02 (dd, J=9.2 Hz, 1H), 8.30 (dd, J=8.4 Hz, 1H), 8.51 (d, J=5.6Hz, 1H), 8.64 (s, 1H), 9.38 (s, 1H), 10.95 (s, 1H). (M+H)⁺ 683.5.

Synthetic Scheme for Exemplary Compound 128

3-(5-(4-(2-(1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Prepared according to the synthetic scheme below using proceduresdescribed for Compound 127.

Compound 128: ¹H NMR (400 MHz, DMSO-d6) δ 1.16-1.23 (m, 3H), 1.40-1.50(m, 2H), 1.61 (br, 1H), 1.76-1.78 (m, 2H), 1.94-1.96 (m, 1H), 2.38-2.41(s, 3H), 2.51-2.56 (m, 4H), 2.82-2.90 (m, 3H), 3.29-3.33 (m, 4H), 3.95(s, 3H), 4.18-4.22 (m, 1H), 4.30-4.39 (m, 3H), 5.02-5.08 (m, 1H), 6.95(d, J=8.8 Hz, 1H), 7.05-7.06 (m, 2H), 7.50-7.69 (m, 3H), 7.91 (s, 1H),8.00 (dd, J=8.8, 2.2 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.48 (d, J=5.8 Hz,1H), 8.62 (d, J=2.0 Hz, 1H), 9.33 (s, 1H), 10.95 (s, 1H). (M+H)⁺ 697.6.

Synthetic Scheme for Exemplary Compound 130

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(3-(4-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)propoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the synthetic scheme below using proceduresdescribed above and common procedures known to those skilled in the art.

Compound 130: ¹H NMR (400 MHz, DMSO-d6): δ 1.74-1.80 (m, 4H), 1.85-1.92(m, 2H), 1.97-2.02 (m, 2H), 2.02-2.15 (m, 2H), 2.54-2.58 (m, 2H),2.67-2.91 (m, 4H), 3.41-3.50 (m, 8H), 3.81-3.88 (m, 2H), 3.98 (s, 3H),4.25 (t, J=7.8 Hz, 2H), 4.44-4.49 (m, 1H), 5.05 (dd, J=5.2, 12.8 Hz,1H), 5.33-5.40 (m, 1H), 6.66 (dd, J=1.6, 8.4 Hz, 1H), 6.80 (d, J=1.2 Hz,1H), 7.63-7.72 (m, 3H), 8.10 (s, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.51 (d,J=4.8 Hz, 2H), 8.92 (s, 1H), 9.39 (s, 1H), 11.06 (s, 1H). (M+H)⁺ 854.6.

Synthetic Scheme for Exemplary Compound 129

2-(2,6-dioxopiperidin-3-yl)-5-((1,1,1-trifluoro-6-(2-(2-(2-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)hexan-2-yl)oxy)isoindoline-1,3-dione

Step 1:6-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexan-2-ol

To a solution of5-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy) pentanal (575mg, 1.47 mmol) [prepared according to the scheme below and usingprocedures described above and common procedures known to those skilledin the art] and CF₃Si(CH₃)₃ (320 mg, 2.21 mmol) in THF was added TBAF(1M, 2.2 mL, 2.20 mmol) at room temperature. The reaction was stirred atroom temperature for 3 hours. After quenched with 1N HCl (3 mL), themixture was extracted with EA (30 mL), washed with brine. The organicphase was dried, concentrated under vacuum. The residue was purified bya silica gel (PE:EA=2:1) to get6-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexan-2-ol(400 mg, 60% yield).

Step 2: 6-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexan-2-yltrifluoromethanesulfonate

To a solution of6-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexan-2-ol(130 mg, 0.28 mmol) and pyridine (67 mg, 0.85 mmol) in DCM was addedTf₂O (120 mg, 0.42 mmol) at 0° C. The resulting solution warmed to roomtemperature for 1 hour. The reaction was diluted with DCM (10 mL),washed with water, brine and concentrated under vacuum to afford6-(2-(2-(2-(5-bromopyridin-2-yloxy)ethoxy)ethoxy)ethoxy)-1,1,1-trifluorohexan-2-yltrifluoromethanesulfonate(160 mg, 96%).

Compound 129: ¹HNMR (400 MHz, CDCl₃): δ 9.25 (s, 1H), 8.48 (s, 1H), 8.39(s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.4Hz, 1H), 7.46 (s, 1H), 7.36-7.41 (m, 2H), 7.19-7.24 (m, 2H), 6.82 (d,J=8.8 Hz, 1H), 4.86-4.91 (m, 1H), 4.58-4.63 (m, 1H), 4.45-4.48 (m, 2H),3.78-3.82 (m, 5H), 3.55-3.80 (m, 9H), 3.39-3.50 (m, 3H), 2.69-2.82 (m,6H), 1.96-2.05 (m, 2H), 1.81-1.89 (m, 2H). (M+H)⁺ 818.5.

Synthetic Scheme for Exemplary Compound 131

2-(2,6-dioxopiperidin-3-yl)-5-((17-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecyl)oxy)isoindoline-1,3-dione

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

Using procedures analogous to those for Compound 131, the following wereprepared: Compound 132.

Synthetic Scheme for Exemplary Compound 133

2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)hexyl)azetidin-1-yl)isoindoline-1,3-dione

Step 1: (6-(benzyloxy)hexyl)magnesium bromide

A suspension of (((6-bromohexyl)oxy)methyl)benzene (10 g, 0.037 mol),magnesium (1.33 g, 0.055 mol) and iodine (200 mg) in anhydroustetrahydrofuran (100 ml) was stirred at 50° C. for 2 hours. Iodinedisappeared and the mixture was stirred for another 1 hour to afford(6-(benzyloxy)hexyl)magnesium bromide (crude) which was used in the nextstep without further purification.

Step 2: tert-butyl3-(6-(benzyloxy)hexyl)-3-hydroxyazetidine-1-carboxylate

To the solution of tert-butyl 3-oxoazetidine-1-carboxylate (5.2 g, 0.031mol) in anhydrous tetrahydrofuran (50 ml) was added(6-(benzyloxy)hexyl)magnesium bromide at 0° C. The resulting mixture wasallowed to warm up to room temperature and stirred at room temperaturefor 16 hours. The mixture was filtered and the filtrate wasconcentrated. The residue was partitioned between ethyl acetate (50 ml)and water (100 ml). The organic layer was collected, washed with brine(30 ml), dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give a crude residue which was purified by silicagel flash chromatography (eluted with 33-50% ethyl acetate in hexane) toafford tert-butyl3-(6-(benzyloxy)hexyl)-3-hydroxyazetidine-1-carboxylate (1.7 g, twosteps 12%) as colorless oil.

Step 3: tert-butyl 3-(6-(benzyloxy)hexylidene)azetidine-1-carboxylate

To a stirred solution of tert-butyl3-(6-(benzyloxy)hexyl)-3-hydroxyazetidine-1-carboxylate (800 mg, 2.2mmol) in toluene (10 ml) was added1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess reagent)(1.57 g, 6.6 mmol). The resulting solution was allowed to warm up to 90°C. and stirred at this temperature for 2 hours. The mixture was pouredinto water (20 ml) and extracted with ethyl acetate (20 ml×2). Thecombined organic layers were washed with brine (20 ml), dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive a crude residue which was purified by silica gel flash columnchromatography (eluted with 30% ethyl acetate in hexane) to affordtert-butyl 3-(6-(benzyloxy)hexylidene)azetidine-1-carboxylate (125 mg,yield 16%) as colorless oil.

Step 4: tert-butyl 3-(6-hydroxyhexyl)azetidine-1-carboxylate

A mixture of tert-butyl3-(6-(benzyloxy)hexylidene)azetidine-1-carboxylate (125 mg, 0.36 mmol),palladium on carbon (10%, 50 mg) in methanol (30 ml) was stirred at roomtemperature for 3 hours under hydrogen atmosphere (hydrogen balloon).TLC showed the reaction was complete. Palladium on carbon was removedthrough filtration and washed with methanol (5 ml×2). The combinedfiltrates were concentrated under reduced pressure to afford tert-butyl3-(6-hydroxyhexyl)azetidine-1-carboxylate (88 mg, yield: 95%) ascolorless oil.

Tert-butyl 3-(6-hydroxyhexyl)azetidine-1-carboxylate was converted tothe final compound,2-(2,6-dioxopiperidin-3-yl)-5-(3-(6-((5-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)pentyl)oxy)hexyl)azetidin-1-yl)isoindoline-1,3-dione,according to the scheme below and using procedures described above andcommon procedures known to those skilled in the art.

Compound 133: 1H NMR (400 Hz, D6-DMSO): δ 1.24-1.35 (m, 7H), 1.46-1.57(m, 8H), 1.72-1.82 (m, 2H), 1.98-2.01 (m, 3H), 2.57-2.74 (m, 3H),2.81-2.99 (m, 2H), 3.57-3.59 (m, 2H), 3.98 (s, 3H), 4.06-4.08 (m, 2H),4.33 (s, 2H), 5.03-5.06 (m, 1H), 6.54-6.66 (m, 1H), 6.69 (s, 1H),6.93-6.95 (m, 1H), 7.57-7.71 (m, 3H), 8.02 (s, 1H), 8.19-8.21 (m, 1H),8.34-8.36 (m, 1H), 8.53-8.58 (m, 1H), 8.66 (s, 1H), 9.41 (s, 1H), 11.08(s, 1H). (M+H)⁺ 757.6.

Synthetic Scheme for Exemplary Compound 134

2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione

Step 1: 3,6-diiodopyridazine

A mixture of 3,6-dichloropyridazine (5.0 g, 34.0 mmol) and sodium iodide(50 g, 0.68 mol) in acetone (50 ml) was stirred at 65° C. for 3 hours.The reaction mixture was quenched with water (100 ml) and extracted withethyl acetate (200 ml×2). The combined organic layers were washed withbrine (200 ml×2), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a residue which was purified by silicagel flash column chromatography (eluted with 40% ethyl acetate inhexane) to afford 3,6-diiodopyridazine (5.4 g, 4.9 mol, 48% yield) asbrown solid.

Step 2: 3-fluoro-6-iodopyridazine

A mixture of 3,6-dichloropyridazine (1 g, 3.0 mmol), cesium fluoride(413 mg, 0.9 mol) in dimethyl sulphoxide (10 ml) was stirred at 140° C.overnight. The reaction mixture was partitioned between water (50 ml)and ethyl acetate (100 ml). The organic layer was collected, washed withbrine (100 ml), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a residue which was purified by silicagel flash column chromatography (eluted with 20% ethyl acetate inhexane) to afford 3-fluoro-6-iodopyridazine (840 mg).

Step 3: 7-(6-((1r,3r)-3-((6-iodopyridazin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole

(1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanol(100 mg, 0.29 mmol), 3-fluoro-6-iodopyridazine (300 mg, 0.10 mmol) in1-methylpyrrolidin-2-one (5 ml) was added sodium hydride (60% in mineraloil) (110 mg, 2.7 mmol) at 0° C. The resulting mixture was allowed towarm up to room temperature for 1 hour. The reaction mixture wasquenched with water (10 ml) at 0° C. and extracted with ethyl acetate(20 ml×3). The combined organic layers were washed with brine (20 ml),dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give a crude residue which was purified by silica gel flashchromatography (eluted with 20% methanol in dichloromethane) to afford7-(6-((1r,3r)-3-((6-iodopyridazin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole(70 mg, 0.13 mmol, yield 44%) as brown solid.

7-(6-((1r,3r)-3-((6-iodopyridazin-3-yl)oxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indolewas converted to the final compound,2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridazin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione,according to the scheme below and using procedures described above (step6 of Compound 73 and step 1 of Compound 180).

Compound 134: ¹HNMR (400 MHz, DMSO-d₆): δ 1.74-1.78 (m, 2H), 1.92-1.95(m, 2H), 2.03-2.07 (m, 1H), 2.54-2.62 (m, 4H), 2.68-2.71 (m, 4H),2.85-2.93 (m, 1H), 3.96 (s, 3H), 4.23-4.27 (m, 2H), 5.09-5.14 (m, 1H),5.45-5.48 (m, 1H), 5.55-5.58 (m, 1H), 7.01 (d, J=8.8 Hz, 1H), 7.24-7.26(m, 1H), 7.36-7.38 (m, 1H), 7.45 (m, 1H), 7.62-7.68 (m, 3H), 7.82 (d,J=8.0 Hz, 1H), 7.99 (s, 1H), 8.21-8.24 (m, 1H), 8.33 (d, J=8.0 Hz, 1H),8.49-8.51 (m, 1H), 8.64-8.65 (m, 1H), 9.37 (s, 1H), 11.12 (s, 1H).(M+H)⁺ 776.5.

Additionally, Compound 149 was prepared from Compound 134 usinghydrogenation procedure described previously for the conversion ofCompound 102 to Compound 110.

Synthetic Scheme for Exemplary Compound 145

2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)methyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione

Prepared according to the schemes below and using procedures describedabove and common procedures known to those skilled in the art.

Compound 135: ¹H NMR (400 MHz, DMSO-d₆): 1.60-1.80 (m, 6H), 1.92-2.07(m, 5H), 2.16-2.26 (m, 3H), 2.34-2.40 (m, 2H), 2.55-2.67 (m, 4H),2.84-2.93 (m, 1H), 3.26-3.31 (m, 4H), 3.78-3.82 (m, 1H), 3.96 (s, 3H),4.18 (t, J=6.0 Hz, 2H), 5.05-5.27 (m, 2H), 6.90-6.94 (m, 1H), 7.33-7.35(m, 1H), 7.42 (s, 1H), 7.60-7.63 (m, 2H), 7.83 (d, J=8.4 Hz, 1H), 7.98(s, 1H), 8.17-8.20 (m, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.51 (d, J=6.0 Hz,1H), 8.62 (s, 1H), 9.36 (s, 1H), 11.12 (s, 1H). (M+H)⁺ 783.6.

Synthetic Scheme for Exemplary Compound 136

2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione

Prepared according to the schemes below and using procedures describedabove and common procedures known to those skilled in the art.

Compound 136: 1HNMR (400 MHz, DMSO-d₆): δ 1.61-1.65 (m, 2H), 1.77-1.80(m, 2H), 1.99-2.08 (m, 4H), 2.14-2.20 (m, 2H), 2.44-2.46 (m, 3H),2.55-2.61 (m, 4H), 2.72-2.76 (m, 1H), 2.85-2.93 (m, 1H), 3.79-3.84 (m,3H), 3.96 (s, 3H), 4.04-4.09 (m, 2H), 4.17-4.20 (m, 2H), 5.10-5.14 (m,2H), 6.93 (d, J=8.4 Hz, 1H), 7.34-7.42 (m, 2H), 7.61-7.65 (m, 2H), 7.83(d, J=8.0 Hz, 1H), 7.99 (s, 1H), 8.18-8.20 (m, 1H), 8.32 (d, J=8.4 Hz,1H), 8.50 (d, J=6.0 Hz, 1H), 8.62 (d, J=0.8 Hz, 1H), 9.37 (s, 1H), 11.12(s, 1H). (M+H)⁺ 797.5.

Synthetic Scheme for Exemplary Compound 137

2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)isoindoline-1,3-dione

Step 1: Benzyl 5-hydroxypentanoate

A mixture of tetrahydro-2H-pyran-2-one (1 g, 10 mmol) and sodiumhydroxide (400 mg, 10 mmol) in water (15 ml) was stirred at 70° C. for16 hours. The mixture was concentrated under reduced pressure to give acrude residue which was dissolved in acetone (20 ml), followed bysequential addition of tetrabutylammonium bromide (161 mg, 0.5 mmol) andbenzyl bromide (2 g, 12 mmol) at room temperature. The mixture wasstirred at 60° C. for 4 hours. TLC showed the reaction was complete. Themixture was concentrated and the residue was partitioned between ethylacetate (30 ml) and water (50 ml). The organic layer was collected,washed with brine (30 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a crude residue which waspurified by silica gel flash chromatography (eluted with 33-50% ethylacetate in hexane) to afford benzyl 5-hydroxypentanoate (500 mg, 24%) aslight yellow solid.

Benzyl 5-hydroxypentanoate was converted to the final compound,2-(2,6-dioxopiperidin-3-yl)-5-((5-(6-(methyl((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)amino)-2-azaspiro[3.3]heptan-2-yl)-5-oxopentyl)oxy)isoindoline-1,3-dione,according to the schemes below and using procedures described above andcommon procedures known to those skilled in the art.

Compound 137: ¹H NMR (400 MHz, DMSO-d6): δ 1.58-1.63 (m, 2H), 1.72-1.77(m, 2H), 2.03-2.11 (m, 3H), 2.33-2.47 (m, 8H), 2.54-2.62 (m, 2H),2.78-2.90 (m, 3H), 3.41-3.48 (m, 3H), 3.75-3.79 (m, 1H), 3.80-3.87 (m,1H), 4.02 (s, 3H), 4.06 (s, 1H), 4.13-4.18 (m, 3H), 5.10-5.14 (m, 1H),5.25-5.28 (m, 1H), 6.96-7.00 (m, 1H), 7.33-7.42 (m, 2H), 7.70 (d, J=8.4Hz, 1H), 7.80-7.84 (m, 2H), 8.06 (s, 1H), 8.23-8.26 (m, 1H), 8.39 (d,J=8.0 Hz, 1H), 8.57-8.67 (m, 2H), 9.49 (s, 1H), 11.12 (s, 1H). (M+H)⁺810.6.

Synthetic Scheme for Exemplary Compound 138

5-((14-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1:5-(difluoromethyl)-7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole

To a solution of 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (500 mg, 1.90 mmol) in dry N,N-dimethylformamide (6 ml) was added sodiumhydride (60% in mineral oil) (380 mg, 9.50 mmol) at 0° C., and theresulting mixture was stirred at room temperature for 30 minutes. Thensodium 2-chloro-2,2-difluoroacetate (580 mg, 3.80 mmol) was added, andthe resulting reaction mixture was stirred at 80° C. for 5 hours. Thereaction mixture was quenched with water (30 ml) at 0° C. and extractedwith ethyl acetate (30 ml). The combined organic layers were washed withbrine (30 ml), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give a residue which was purified by silicagel flash chromatography (eluted with 50% ethyl acetate in hexane) toafford5-(difluoromethyl)-7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (35mg, yield 6%) as yellow solid.

5-(Difluoromethyl)-7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole wasconverted to the final compound,5-((14-((5-(5-(difluoromethyl)-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione,according to the scheme below using procedures described above andcommon procedures known to those skilled in the art.

Compound 138: ¹H NMR (400 MHz, DMSO-d6): δ 2.01-2.04 (m, 1H), 2.56-2.67(m, 2H), 2.83-2.93 (m, 1H), 3.52-3.59 (m, 12H), 3.78 (s, 4H), 4.29 (s,2H), 4.45 (s, 2H), 5.11 (d, J=12.8 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 7.34(d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.76-7.83 (m, 3H), 8.14-8.18 (m, 2H),8.36-8.50 (m, 2H), 8.61-8.65 (m, 2H), 9.49 (s, 1H), 11.11 (s, 1H).(M+H)⁺ 788.5.

Synthetic Scheme for Exemplary Compound 139

2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-fluoro-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 140

2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

Step 1: 2-fluoro-5-iodo-3-methylpyridine

A mixture of 6-fluoro-5-methylpyridin-3-amine (300 mg, 2.4 mmol) inN,N-dimethylacetamide (10 ml) was added potassium iodide (395 mg, 2.4mmol), iodine (306 g, 1.2 mmol), copper(I) iodide (137 mg, 0.72 mmol)and tert-butyl nitrite (1.7 g, 14.4 mmol) was stirred at 90° C. for 2hours. The reaction mixture was quenched with water (30 ml) andextracted with ethyl acetate (20 ml). The combined organic layers werewashed with brine (30 ml), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give a residue which was purifiedby silica gel flash chromatography (eluted with 10% ethyl acetate inhexane) to afford 2-fluoro-5-iodo-3-methylpyridine (350 mg, yield 62%)as white solid.

2-fluoro-5-iodo-3-methylpyridine was converted to the final compound,2-(2,6-dioxopiperidin-3-yl)-5-((14-((3-methyl-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione,according to the scheme below using procedures described above andcommon procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 141

2-(2,6-dioxopiperidin-3-yl)-5-((6-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyrimidin-2-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

Additionally, Compound 151 was prepared from Compound 141 usinghydrogenation procedure described previously for the conversion ofCompound 102 to Compound. 110.

Synthetic Scheme for Exemplary Compound 142

2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 143

2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-6-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione

Step 1: 6-chloro-3-iodo-2-(trifluoromethyl)pyridine

To a solution of lithium diisopropylamide (2 M in THF, 3.03 mmol) intetrahydrofuran (15 ml) was added a solution of2-chloro-6-(trifluoromethyl)pyridine (500 mg, 2.75 mmol) intetrahydrofuran (5 ml) at −65° C. under nitrogen atmosphere. The darkbrown solution was stirred at −65° C. for 30 minutes. To the reactionmixture was added a solution of iodine (0.7 g, 2.75 mmol) intetrahydrofuran (5 ml) was added at −65° C. within 20 minutes. Afteradditional 20 minutes stirring at the same temperature, the reactionmixture was quenched with hydrochloride acid (2M, 6 ml) at 0° C. andstirred for 20 minutes. The reaction mixture was extracted with ethylacetate (30 ml). The combined organic layers were washed with brine (30ml), dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give a residue which was purified by silica gel flashchromatography (eluted with 1% ethyl acetate in hexane) to afford6-chloro-3-iodo-2-(trifluoromethyl)pyridine (316 mg, yield 37%) as brownoil.

6-Chloro-3-iodo-2-(trifluoromethyl)pyridine was converted to the finalcompound,2-(2,6-dioxopiperidin-3-yl)-5-((14-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)-6-(trifluoromethyl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)isoindoline-1,3-dione,according to the scheme below using procedures described above andcommon procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 146

2-(2,6-dioxopiperidin-3-yl)-5-((6-(6-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-3-yl)hex-5-yn-1-yl)oxy)isoindoline-1,3-dione

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 152

2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)azetidin-3-yl)oxy)isoindoline-1,3-dione

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 150

Step 1:2-[5-(3-benzyloxycyclobutoxy)-2,2-difluoro-pentoxy]tetrahydropyran

To a solution of 3-benzyloxycyclobutanol (2.59 g, 14.53 mmol, 1.10 eq)in N,N-dimethylformamide (100 mL) was added sodium hydride (581 mg,14.53 mmol, 60% in mineral oil, 1.10 eq) at 0° C. under nitrogen. Themixture was stirred at 0° C. for 0.5 hours and added a solution of(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) 4-methylbenzenesulfonate(5.0 g, 13.21 mmol, 1.00 eq) [prepared as described for Compound 171] inN,N-dimethylformamide (20 mL) dropwise at 0° C. The reaction mixture wasstirred at 60° C. for 6 hours. The mixture was cooled to 25° C. andpoured into ice-water (w/w=1/1) (30 mL) and stirred for 15 minutes. Theaqueous phase was extracted with ethyl acetate (100 mL×3). The combinedorganic phase was washed with brine (100 mL×3), dried with anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel chromatography (Petroleum ether/Ethylacetate=1/0, 20/1) to afford2-[5-(3-benzyloxycyclobutoxy)-2,2-difluoro-pentoxy]tetrahydropyran (1.75g, 4.21 mmol, 32% yield, 92% purity) as a colorless oil.

Step 2: 3-(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy)cyclobutanol

To a solution of2-[5-(3-benzyloxycyclobutoxy)-2,2-difluoro-pentoxy]tetrahydropyran (1.75g, 4.55 mmol, 1.00 eq) in methanol (30 mL) was added palladium onactivated carbon catalyst (1.0 g, 10% purity) under nitrogen. Thesuspension was degassed under vacuum and purged with hydrogen severaltimes. The mixture was stirred under hydrogen (15 psi) at 25° C. for 16hours. The reaction mixture was filtered and the filter wasconcentrated. The crude product was purified by silica gelchromatography (Petroleum ether/Ethyl acetate=10:1 to 1:1) to give3-(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy)cyclobutanol (1.2 g,4.08 mmol, 90% yield) as a colorless oil.

Step 3:5-Bromo-2-[3-(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy)cyclobutoxy]pyridine

To a mixture of3-(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy)cyclobutanol (1.2 g,4.08 mmol, 1.00 eq) and 5-bromopyridin-2-ol (1.06 g, 6.12 mmol, 1.50 eq)in toluene (60 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.54 g,6.12 mmol, 1.50 eq) and tributylphosphane (1.24 g, 6.12 mmol, 1.50 eq)in one portion at 0° C. under nitrogen. The mixture was stirred at 110°C. for 16 hours. The mixture was cooled to 25° C. and concentrated atreduced pressure at 45° C. The residue was poured into ice-water(w/w=1/1) (30 mL) and stirred for 15 minutes. The aqueous phase wasextracted with ethyl acetate (50 mL×3). The combined organic phase waswashed with brine (50 mL×2), dried with anhydrous sodium sulfate,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography (Petroleum ether/Ethyl acetate=100/1, 50/1).5-Bromo-2-[3-(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy)cyclobutoxy]pyridine(1.36 g, 3.02 mmol, 74.0% yield) was obtained as a yellow oil.

Step 4: 5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentan-1-ol

To a mixture of5-bromo-2-[3-(4,4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy)cyclobutoxy]pyridine (1.1 g, 2.44 mmol, 1.00 eq) in tetrahydrofuran (25mL) was added hydrogen chloride (4 M, 10 mL, 16.38 eq) in one portionunder nitrogen. Then the mixture was stirred at 25° C. for 1 hour. Themixture was poured into saturated sodium hydrogencarbonate (20 mL) andstirred for 15 minutes. The aqueous was extracted with ethyl acetate (50mL×3). The combined organic phase was washed with brine (50 mL×3), driedwith anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=10/1, 5/1) to afford 5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentan-1-ol (700 mg, 1.91 mmol, 78% yield) asa colorless oil.

Step 5:[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentyl]trifluoromethanesulfonate

To a mixture of5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentan-1-ol (400mg, 1.09 mmol, 1.00 eq) and triethylamine (552 mg, 5.46 mmol, 5.00 eq)in dichloromethane (10 mL) was trifluoromethanesulfonyl chloride (368mg, 2.18 mmol, 2.00 eq) at 0° C. under nitrogen. After the addition hadfinished, the reaction mixture was stirred at 25° C. for 1 hour. Themixture was concentrated in vacuum at 40° C. The residue was purified bysilica gel chromatography (Petroleum ether/Ethyl acetate=5/1) to afford[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentyl]trifluoromethanesulfonate (465 mg, 0.93 mmol, 85% yield) as a colorlessoil.

Step 6: tert-butyl6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione(300 mg, 1.09 mmol, 1.00 eq) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate; oxalic acid (317 mg, 0.65mmol, 0.60 eq) in (methylsulfinyl)methane (5 mL) was addedN,N-diisopropylethylamine (561 mg, 4.34 mmol, 4.00 eq) in one portionunder nitrogen. The mixture was heated to 120° C. and stirred for 16hours. The mixture was poured into ice-water (w/w=1/1) (30 mL) andstirred for 10 minutes. The aqueous phase was extracted with ethylacetate (50 mL×3). The combined organic phase was washed with brine (50mL×3), dried with anhydrous sodium sulfate, filtered and concentrated invacuum. The residue was triturated by Petroleum ether: Ethyl acetate(1:1, 50 mL) to afford tert-butyl6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate(420 mg, 0.92 mmol, 85% yield) as a yellow solid.

Step 7:5-(2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

A mixture of tert-butyl6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate(420 mg, 0.92 mmol, 1.00 eq) in trifluoroacetic acid (1 mL) anddichloromethane (10 mL) was stirred at 25° C. for 1 hour under nitrogen.TLC showed the reaction was completed. The mixture was concentrated inreduced pressure at 45° C. The mixture was purified by semi-preparativereverse phase HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 5ACN %-30ACN %, 15 min; 50%min) to afford5-(2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dioneformate (260 mg, 0.64 mmol, 70% yield) as a yellow solid.

Step 8:5-[6-[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentyl]trifluoromethanesulfonate(460 mg, 0.92 mmol, 1.00 eq) and5-(2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dioneformate (443 mg, 1.11 mmol, 1.20 eq) in acetonitrile (25 mL) and(methylsulfinyl)methane (5 mL) was added potassium carbonate (255 mg,1.85 mmol, 2.00 eq) in one portion at 25° C. under nitrogen. The mixturewas stirred at 25° C. for 10 hours. LC-MS showed[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentyl]trifluoromethanesulfonatewas consumed completely and one main peak with desired MS was detected.The suspension was filtered and concentrated in vacuum. The residue wasdiluted with ethyl acetate (100 mL), washed with brine (30 mL×3), driedwith anhydrous sodium sulfate, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (Petroleum ether/Ethylacetate=1/1, 1/3) to afford5-[6-[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(320 mg, 0.45 mmol, 49% yield) as a yellow solid.

Step 9:5-[6-[2,2-difluoro-5-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

5-[6-[5-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]-2,2-difluoro-pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(200 mg, 0.28 mmol, 1.00 eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(86 mg, 0.34 mmol, 1.20 eq), potassium acetate (55 mg, 0.56 mmol, 2.00eq) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex (23 mg, 0.02 mmol, 0.10 eq) in dioxane (10 mL)was de-gassed and then heated to 90° C. for 2 hours under nitrogen. Thereaction mixture was filtered and the filter was concentrated. The crudeproduct was purified by prep-TLC (dichloromethane:methanol=20:1) to give5-[6-[2,2-difluoro-5-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(200 mg, 0.26 mmol, 94% yield) as a yellow oil.

Step 10:5-[6-[2,2-difluoro-5-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

5-[6-[2,2-difluoro-5-[3-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(200 mg, 0.26 mmol, 1.00 eq), 7-bromo-5-methyl-pyrido[4,3-b]indole (69mg, 0.26 mmol, 1.00 eq), sodium carbonate (56 mg, 0.53 mmol, 2.00 eq)and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex (21 mg, 0.02 mmol, 0.10 eq) inN,N-dimethylformamide (5 mL) and water (0.5 mL) was de-gassed and thenheated to 90° C. for 2 hours under nitrogen. LCMS showed the reactionwas completed. The mixture was cooled to 25° C. and filtered. Theresidue was diluted with ethyl acetate (50 mL), washed with brine (30mL×3), dried over anhydrous sodium sulfate, concentrated in vacuum. Themixture was purified by semi-preparative reverse phase HPLC (18-48%acetonitrile+0.225% formic acid in water, over 10 min). Then thecollected fraction was concentrated to remove most of the acetonitrile.The solution was lyophilized.5-[6-[2,2-difluoro-5-[3-[[5-(5-methylpyrido[4,3-b]indol-7-yl)-2-pyridyl]oxy]cyclobutoxy]pentyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dioneformate (21.6 mg, 0.02 mmol, 9% yield, 95% purity) was obtained as ayellow solid.

¹H NMR: (400 MHz, DMSO-d₆) δ: 10.95 (s, 1H), 9.14 (br s, 1H), 8.15 (s,1H), 7.52 (d, J=9.0 Hz, 1H), 7.18-7.04 (m, 5H), 6.83 (d, J=6.7 Hz, 2H),6.65 (d, J=8.5 Hz, 1H), 6.61 (s, 1H), 6.54-6.47 (m, 3H), 6.26 (d, J=8.5Hz, 2H), 5.05 (dd, J=5.0, 13.3 Hz, 1H), 4.38-4.26 (m, 1H), 4.24-4.11 (m,1H), 3.78 (br t, J=6.5 Hz, 4H), 3.54-3.31 (m, 3H), 3.03-2.83 (m, 8H),2.62-2.52 (m, 3H), 2.47-2.31 (m, 1H), 2.21-2.04 (m, 3H), 2.01-1.87 (m,3H), 1.71 (br d, J=10.7 Hz, 2H). (M+H)⁺ 804.5.

Synthetic Scheme for Exemplary Compound 153

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3,3,3-trifluoro-2-((5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)propyl)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the schemes below using procedures described aboveand common procedures known to those skilled in the art.

Using procedures of Compound 153 the following were prepared: Compound154.

Synthetic Scheme for Exemplar Compound 155

2-(2,6-dioxopiperidin-3-yl)-5-(3-((5-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)pyridin-2-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the schemes below using procedures described aboveand common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 156

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the schemes below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 157

2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione

Step 1: (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanecarboxylic

To a solution of (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanecarbaldehyde(70 mg, 0.20 mmol) in tetrahydrofuran (1 ml) and water (1 ml) was addedsodium chlorite (62 mg, 0.63 mmol), sodium dihydrogen phosphatedehydrate (168 mg, 1.08 mmol) and 2-methylbut-2-ene (233 mg, 3.33 mmol),then the mixture was stirred at room temperature overnight. TLC showedthe reaction was complete. The reaction mixture was diluted withdichloromethane (20 ml), washed with water (10 ml×3), brine (10 ml),dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give crude (1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanecarboxylicacid as yellow solid.

(1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutanecarboxylicacid was converted to the final compound,2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)butoxy)isoindoline-1,3-dione,according to the scheme below and using procedure described above forCompound 153.

Synthetic Scheme for Exemplary Compound 158

2-(2,6-dioxopiperidin-3-yl)-5-(2-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridazin-4-yl)oxy)ethoxy)isoindoline-1,3-dione

Step 1: 5-(2-(benzyloxy)ethoxy)-3-chloropyridazine

To a stirred solution of 2-(benzyloxy)ethanol (440 mg, 2.895 mmol) and3,5-dichloropyridazine (428 mg, 2.895 mmol) in 1-methyl-2-pyrrolidinone(5 ml) was added sodium hydride (60% in oil) (347 mg, 8.68 mmol) at 0°C. Then the mixture was stirred at room temperature for 1 hour. Thereaction mixture was quenched with aqueous ammonium chloride solution(15 ml) at 0° C., and extracted with ethyl acetate (20 ml×3). Theorganic layer was with brine (20 ml×2), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give a crude residuewhich was purified by silica gel flash column chromatography (elutedwith 15% ethyl acetate in hexane) to give5-(2-(benzyloxy)ethoxy)-3-chloropyridazine (680 mg, 89% yield) as lightbrown oil.

Step 2: (1r,3r)-3-((1-(5-(2-(benzyloxy)ethoxy)pyridazin-3-yl)piperidin-4-yl)oxy)cyclobutanol

To the mixture of 5-(2-(benzyloxy)ethoxy)-3-chloropyridazine (240 mg,0.910 mmol) and (1r, 3r)-3-(piperidin-4-yloxy)cyclobutanol (155 mg,0.910 mmol) [prepared via hydrogenation of (1r,3r)-3-((1-benzylpiperidin-4-yl)oxy)cyclobutan-1-ol as described in step5 of Compound 65 but without di-tert-butyl carbonate present] in toluene(5 ml) were added Pd₂(dba)₃ (83 mg, 0.091 mmol),(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (56 mg, 0.091 mmol)and cesium carbonate (739 mg, 2.27 mmol) under nitrogen. Then themixture was heated to 90° C. overnight. TLC showed the reaction wascomplete. The reaction mixture was extracted with ethyl acetate (30ml×3). The organic layer was with brine (10 ml×2), dried over anhydroussodium sulfate and concentrated under reduced pressure to give a cruderesidue which was purified by silica gel flash column chromatography(eluted with 8% ethyl acetate in hexane) to give (1r,3r)-3-((1-(5-(2-(benzyloxy)ethoxy)pyridazin-3-yl)piperidin-4-yl)oxy)cyclobutanol(135 mg, 38% yield) as light yellow oil.

(1r,3r)-3-((1-(5-(2-(benzyloxy)ethoxy)pyridazin-3-yl)piperidin-4-yl)oxy)cyclobutanolwas converted to the final compound,2-(2,6-dioxopiperidin-3-yl)-5-(2-((6-(4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)piperidin-1-yl)pyridazin-4-yl)oxy)ethoxy)isoindoline-1,3-dione,according to the scheme below and using procedures described above andcommon procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 159 and Compound 160

2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-((1s,3s)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 161

2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Based on the general approach of the Compound 163 and using commonprocedures known to those skilled in the art additional compounds wereprepared: 162, 165, 178, 181, and 182.

Synthetic Scheme for Exemplary Compounds 165 and 166

5-((5-((1-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

5-((5-((1-((1s,3s)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutane-1-carbonyl)piperidin-4-yl)oxy)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compounds 167 and 168

2-(2,6-dioxopiperidin-3-yl)-5-(3-((3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)prop-2-yn-1-yl)oxy)azetidin-1-yl)isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(5-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)propoxy)pyridin-2-yl)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 169

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)oxetan-3-yl)methoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 174

2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)butoxy)isoindoline-1,3-dione

Step 1: bicyclo[1.1.1]pentane-1,3-diyldimethanol

To a solution of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (500mg, 2.72 mmol) in tetrahydrofuran (5 ml) was added lithium aluminumhydride (419 mg, 10.87 mmol) at 0° C., and the resulting mixture wasstirred at room temperature for 2 hours. TLC showed the reaction wascomplete. The reaction mixture was quenched with water (1 ml), sodiumhydroxide (2 ml, 10% in water) and water (1 ml). The solid was removedthrough filtration, and the filtrate was dried over anhydrous sodiumsulfate, concentrated under reduced pressure to afford to affordbicyclo[1.1.1]pentane-1,3-diyldimethanol (256 mg crude, yield 70%) aslight yellow oil.

Bicyclo[1.1.1]pentane-1,3-diyldimethanol was converted to the finalcompound, 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)butoxy)isoindoline-1,3-dione,according to the scheme below and using procedures described above andcommon procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 175

2-(2,6-dioxopiperidin-3-yl)-5-((5-((3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pentyl)oxy)isoindoline-1,3-dione

Step 1: 3-(Hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate

To a solution of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (1 g,5.43 mmol) in tetrahydrofuran (10 ml) was added lithium borohydride (120mg, 5.43 mmol) at 0° C. under nitrogen. The mixture was allowed to warmup to room temperature and stirred at room temperature for 5 hours. Themixture was quenched with aqueous hydrochloride acid (1N) till pH 3-4,and extracted with dichloromethane (10 ml×2). The organic layers werecombined, washed with brine (10 ml), dried over sodium sulfate andconcentrated under reduced pressure to give a crude residue which waspurified by silica gel flash chromatography (eluted with 20-33% ethylacetate in hexane) to afford methyl3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (400 mg, 47%) ascolorless oil.

3-(Hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate was converted tothe final compound,2-(2,6-dioxopiperidin-3-yl)-5-((5-((3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)methoxy)pentyl)oxy)isoindoline-1,3-dione,according to the schemes below and using procedures described above andcommon procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 176

5-(3-(3-(3-((1r,3r)-3-((5-(8,9-difluoro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Prepared according to the schemes below and using procedures describedabove for Compound 104 (in modified sequence) and common proceduresknown to those skilled in the art.

Synthetic Scheme for Exemplary Compound 177

3-(5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Step 1: 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A mixture of 7-(6-((1r,3r)-3-(3-(3-(azetidin-3-yloxy)propoxy)propoxy)cyclobutoxy)pyridin-3-yl)-5-methyl-5H-pyrido[4,3-b]indole(crude, 0.390 mmol) [prepared as described for Compound 104],N-ethyl-N-isopropylpropan-2-amine (86 mg, 1.17 mmol) and methyl2-cyano-4-fluorobenzoate (90 mg, 0.468 mmol) in 1-methyl-2-pyrrolidinone(3 ml) was stirred at 90° C. for 16 hour. TLC showed the reaction wascomplete. The reaction mixture was partitioned between ethyl acetate (20ml) and water (30 ml). The organic layer was collected, washed withbrine (20 ml), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to give a crude residue which was purified bysilica gel flash column chromatography (eluted with 2-4% methanol indichloromethane) to afford 5-(3-(3-(3-((1r,3r)-3-((5-(5H-pyrido[4,3-b]indol-7-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(160 mg, yield 61%) as light yellow oil.

Step 2: Methyl 2-formyl-4-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)benzoate

To the mixture of methyl 2-cyano-4-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)benzoate(160 mg, 0.237 mmol) in pyridine (3 ml)-water (1.5 ml)-acetic acid (1.5ml) was added sodium hypophosphite (125 mg, 1.179 mmol) and Raney nickel(85% in water) (300 mg) at room temperature. The resulting mixture wasstirred at 50° C. for 2 hours. The mixture was diluted with ethylacetate (30 ml), washed with water (30 ml×2), diluted hydrochloride acidsolution (1 N, 30 ml), brine (50 ml), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give a crude residuewhich was purified by silica gel flash chromatography (eluted with 2-5%methanol in dichloromethane:) to afford methyl 2-formyl-4-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)benzoate(90 mg, yield 56%) as brown oil.

Step 3: 3-(5-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of 3-aminopiperidine-2,6-dione (32 mg, 0.199mmol)N-ethyl-N-isopropylpropan-2-amine (34 mg, 0.199 mmol), acetic acid(0.5 ml) and methyl 2-formyl-4-(3-(3-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propoxy)propoxy)azetidin-1-yl)benzoate(90 mg, 0.133 mmol) in methanol (5 ml) was stirred at room temperaturefor 15 min. Then sodium cyanoborohydride (16 mg, 0.400 mmol) was addedand stirred at room temperature overnight. TLC showed the reaction wascomplete. The reaction mixture was partitioned between dichloromethane(30 ml) and water (10 ml), the organic layer was collected, washed withbrine (10 ml×2), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to give a crude residue which was purified byPrep-TLC (8% methanol in ethyl acetate) to afford the title compound (50mg, yield 50%) as white solid.

¹H NMR (400 MHz, DMSO-d6): δ 1.71-1.80 (m, 4H), 1.90-1.93 (m, 1H),2.28-2.37 (m, 3H), 2.40-2.44 (m, 2H), 2.56-2.57 (m, 1H), 2.83-2.92 (m,1H), 3.37 (t, J=6.0 Hz, 2H), 3.43-3.48 (m, 6H), 3.67-3.70 (m, 2H), 3.95(s, 3H), 4.11-4.19 (m, 4H), 4.23-4.27 (m, 1H), 4.42-4.44 (m, 1H),4.99-5.03 (m, 1H), 5.31-5.34 (m, 1H), 6.46-6.49 (m, 2H), 6.94 (d, J=8.8Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.60-7.63 (m, 2H), 7.97 (s, 1H),8.17-8.20 (m, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.50 (d, J=6.0 Hz, 1H), 8.64(d, J=2.0 Hz, 1H), 9.37 (s, 1H), 10.92 (s, 1H). (M+H)⁺ 759.6.

Synthetic Scheme for Exemplary Compound 184

2-(2,6-dioxopiperidin-3-yl)-5-((7-(3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)heptyl)oxy)isoindoline-1,3-dione

Step 1: (6-(benzyloxy)hexyl)triphenylphosphonium bromide

A mixture of (((6-bromohexyl)oxy)methyl)benzene (2.7 g, 10 mmol) andtriphenylphosphine (2.6 g, 10 mmol) in acetonitrile (10 ml) was stirredat reflux for 40 hours. The reaction mixture was allowed to cool to roomtemperature and concentrated under reduced pressure to afford(6-(benzyloxy)hexyl)triphenylphosphonium bromide (5 g, yield: 94%) ascolorless oil.

Step 2: Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate

To a stirred solution of methyl3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (156 mg, 1 mmol) indichloromethane (10 ml) was added Dess-Martin periodinane (840 mg, 2.0mmol) at 0° C. The resulting reaction mixture was allowed to warm up toroom temperature and stirred at this temperature for additional 1 h. Thereaction mixture was quenched with aqueous solution of sodium sulfite(10 ml) and extracted with dichloromethane (20 ml×2), washed with brine(20 ml×2), dried over anhydrous sodium sulfate, and concentrated underreduced pressure to afford a crude residue which was purified by silicagel flash chromatography (eluted with 20% ethyl acetate in hexane) toafford methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (110 mg, yield70%) as colorless oil.

Step 3: Methyl3-(7-(benzyloxy)hept-1-en-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

To a solution of (6-(benzyloxy)hexyl)triphenylphosphonium bromide (373mg, 0.70 mmol) in anhydrous tetrahydrofuran (6 ml) was addedn-butyllithium (2.5 M in hexane) (0.28 mL, 0.7 mmol) dropwise at −20° C.and the resulting mixture was stirred at the same temperature for 30min. Methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (90 mg, 0.58mmol) in anhydrous tetrahydrofuran (1 ml) was added dropwise. Theresulting reaction mixture was warmed to room temperature slowly andstirred at the same temperature for 30 min. The reaction mixture wasquenched with water (10 ml) at 0° C. and extracted with ethyl acetate(20 ml×2). The combined organic layers were washed with brine (20 ml),dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give a residue which was purified by silica gel flashchromatography (eluted with 10% ethyl acetate in hexane) to affordmethyl3-(7-(benzyloxy)hept-1-en-1-yl)bicyclo[1.1.1]pentane-1-carboxylate (56mg, yield 29%) as colorless oil.

Methyl3-(7-(benzyloxy)hept-1-en-1-yl)bicyclo[1.1.1]pentane-1-carboxylate wasconverted to the final compound,2-(2,6-dioxopiperidin-3-yl)-5-((7-(3-(3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)azetidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)heptyl)oxy)isoindoline-1,3-dione,according to the schemes below and using procedures described above andcommon procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 185

(2S,4R)—N-(2-(2-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Using procedures analogous to those for Compound 185 the following wereprepared: Compounds 186, 187, 196, 201.

Synthetic Scheme for Exemplary Compound 193

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-oxoethoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the schemes below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 195

5-((14-((5-(4-chloro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: 3-bromo-5-chloropyridin-4-amine

To a solution of 3-chloropyridin-4-amine (10 g, 77.78 mmol) inacetonitrile (100 ml) was added N-bromosuccinimide (14.5 g, 81.67 mmol)at room temperature, and the resulting mixture was stirred at 60° C. forovernight under nitrogen. The reaction mixture was quenched with water(50 ml) and extracted with ethyl acetate (50 ml×2). The combined organiclayers were washed with brine (50 ml×2), dried over anhydrous sodiumsulfate, and concentrated to give a residue which was purified by silicagel flash chromatography (eluted with 20-50% ethyl acetate in hexane) toafford 3-bromo-5-chloropyridin-4-amine (8.8 g, yield 54%) as whitesolid.

Step 2: 3-(4-bromophenyl)-5-chloropyridin-4-amine

A mixture of 3-bromo-5-chloropyridin-4-amine (5 g, 24.10 mmol),bis(pinacolato)diboron (12 g, 48320 mmol), potassium acetate (4.7 g,48.20 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride (3.5 g, 4.82 mmol) in dioxane (100 ml) wasstirred at 90° C. overnight under nitrogen. TLC showed the reaction wascomplete. To this mixture solution was added 1,4-dibromobenzene (11.4 g,48.20 mmol), potassium carbonate (6.7 g, 48.20 mmol) and water (30 ml).tetrakis(triphenylphosphine)palladium (1.4 g, 1.21 mmol) was added andthe mixture was stirred at 90° C. overnight under nitrogen. The reactionmixture was filtered and the filtrate was partitioned between ethylacetate (100 ml) and water (100 ml), the organic layer was washed withbrine (20 ml×2), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to give a crude residue which was purified bysilica gel flash chromatography (eluted with 20-50% ethyl acetate inhexane) to afford 3-(4-bromophenyl)-5-chloropyridin-4-amine (2.3 g,yield 34%) as yellow solid.

Step 3: 4-azido-3-(4-bromophenyl)-5-chloropyridine

To a solution of 3-(4-bromophenyl)-5-chloropyridin-4-amine (2.5 g, 8.8mmol) in 2,2,2-trifluoroacetic acid (10 ml) was added sodium nitrite(1.5 g, 22.0 mmol) at 0° C. during 20 min, and the reaction mixture wasstirred at 0° C. for 1 hour. To the reaction mixture was added sodiumazide (1.43 g, 22.0 mmol) at 0° C.; the resulting mixture was allowed towarm up to room temperature and stirred overnight. The reaction mixturewas basified with sodium carbonate till pH 8, and partitioned betweenethyl acetate (30 ml) and water (50 ml). The organic layer wascollected, and the aqueous layer was extracted with ethyl acetate (30ml×2). The combined organic layers were washed with brine (20 ml), driedover anhydrous sodium sulfate, and concentrated under reduced pressureto give a crude residue which was purified by silica gel flashchromatography (eluted with 30% ethyl acetate in hexane) as4-azido-3-(4-bromophenyl)-5-chloropyridine (850 mg, yield 31%) as yellowsolid.

Step 4

A mixture of 4-azido-3-(4-bromophenyl)-5-chloropyridine (850 mg, 2.75mmol) in decalin (10 ml) was stirred in a sealed tube at 150° C. for 10hours. After cooling to room temperature, the reaction mixture wastriturated with hexane (20 ml). The resulting solid was collected byfiltration and dried under vacuum to afford7-bromo-4-chloro-5H-pyrido[4,3-b]indole (600 mg, yield 77%) as yellowsolid which was used in next step directly without further purification.

7-bromo-4-chloro-5H-pyrido[4,3-b]indole was converted to the finalcompound,5-((14-((5-(4-chloro-5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione,according to the scheme below and using procedures described above andcommon procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 197

5-(6-((2,2-difluoro-5-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)pentyl)oxy)-2-azaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 199

3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butoxy)methyl)-N-methyl-N-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutyl)bicyclo[1.1.1]pentane-1-carboxamide

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 202

2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methoxy)-N-methyl-N-(3-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)propyl)acetamide

Prepared according to the schemes below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplar Compound 203

2-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)nicotinonitrile

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 207

5-((14-((5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: (E)-1,1,1-trichloro-4-ethoxy-but-3-en-2-one

To a solution of 2,2,2-trichloroacetyl chloride (31.52 g, 173.36 mmol,19 mL, 1 eq) was added dropwise ethyl vinyl ether (25 g, 346.71 mmol, 33mL, 2 eq) at 0° C. After addition, the mixture was stirred at thistemperature for 5 h, and then the mixture was warmed to 25° C. for 16 h.The mixture was stirred at 130° C. under reduced pressure to let gas(hydrogen chloride) evaporate to form a deep black color solution. Theprocess required for 1 h or waited until no gas came out. The residuewas concentrated under reduced pressure. The crude product(E)-1,1,1-trichloro-4-ethoxy-but-3-en-2-one (39.3 g, crude) was obtainedas a black oil.

Step 2: 2-(trichloromethyl)pyrimido[1,2-a]benzimidazole

To a mixture of (E)-1,1,1-trichloro-4-ethoxy-but-3-en-2-one (39.2 g,180.25 mmol, 1.09 eq) and 1H-benzimidazol-2-amine (22 g, 165.23 mmol, 1eq) in toluene (500 mL) was added triethylamine (20.06 g, 198.27 mmol,27 mL, 1.2 eq) in one portion at 25° C. under nitrogen. The mixture wasstirred at 120° C. for 4 h. The mixture was cooled to 25° C. andconcentrated under reduced pressure at 55° C. The crude product2-(trichloromethyl)pyrimido[1,2-a]benzimidazole (56.3 g, crude) wasobtained as brown solid.

Step 3: Pyrimido[1,2-a]benzimidazol-2-ol

To a mixture of 2-(trichloromethyl)pyrimido[1,2-a]benzimidazole (55.2 g,192.64 mmol, 1 eq) in acetonitrile (950 mL) was added sodium hydroxide(10.2 g, 255.02 mmol, 1.32 eq) in Water (246 mL) in one portion at 20°C. under nitrogen. The mixture was stirred at 100° C. for 2 h. Themixture was cooled to 25° C. and concentrated in reduced pressure at 55°C. Ice was added to the resulting residue, and the pH of the solutionwas adjusted to 8 with hydrochloric acid (1 N, 130 mL). The solid wasfiltered, and dried under high vacuum. The filter was cooled to 10° C.,some precipitate was formed, the cake was collected by filtered andconcentrated under reduced pressure to give a residue. Compoundpyrimido[1,2-a]benzimidazol-2-ol (9.3 g, 50.22 mmol, 26% yield) wasobtained as a yellow solid, and crude product (about 7.3 g) wasobtained.

Step 4: 2-Bromopyrimido[1,2-a]benzimidazole

To a solution of pyrimido[1,2-a]benzimidazol-2-ol (0.5 g, 2.70 mmol, 1eq) in 1,1-dichloroethane (18 mL) and N,N-dimethylformamide (0.18 mL)was added phosphoryl tribromide (1.55 g, 5.40 mmol, 2 eq) in one portionat 20° C. under nitrogen. The mixture was stirred at 100° C. for 6 h.The mixture was cooled to 25° C. and concentrated under reduced pressureat 45° C. The residue was poured into ice-water (w/w=1/1, 30 mL) andstirred for 10 min. The aqueous phase was adjusted to pH=8 with asaturated aqueous solution of sodium bicarbonate. During this period,some precipitate was formed. The cake was collected by filtration anddried under high vacuum. The crude product2-bromopyrimido[1,2-a]benzimidazole (0.65 g, crude) was obtained as ayellow solid.

2-Bromopyrimido[1,2-a]benzimidazole was converted to the final compound,5-((14-((5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione,according to the scheme below and using procedures described above andcommon procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 208

2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((1-(5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)azetidin-3-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 209

2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-((3-(((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)ethoxy)ethoxy)isoindoline-1,3-dione

Prepared according to the scheme below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 210

2-(2,6-dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperazin-1-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione

Step 1: tert-Butyl4-(5-methylpyrido[4,3-b]indol-7-yl)piperazine-1-carboxylate

To a solution of 7-bromo-5-methyl-pyrido[4,3-b]indole (1 g, 3.83 mmol, 1eq) and tert-butyl piperazine-1-carboxylate (2.14 g, 11.49 mmol, 3 eq)in dioxane (20 mL) was added(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (71 mg, 0.11 mmol,0.03 eq), cesium carbonate (3.74 g, 11.49 mmol, 3 eq) and palladium(II)acetate (86 mg, 0.38 mmol, 0.1 eq) under nitrogen, then degassed undervacuum and purged with nitrogen three times. The mixture was stirred at100° C. for 16 hours. The reaction mixture was concentrated to removesolvent and then extracted with ethyl acetate (80 mL×3). The combinedorganic layers were washed with brine 30 mL, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=2/1 to dichloromethane/methanol=10/1) togive crude product, the crude product was purified by semi-preparativereverse phase HPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobilephase: [water (0.225% FA)-ACN]; B %: 27%-52%, 30; 79% min). tert-Butyl4-(5-methylpyrido[4,3-b]indol-7-yl)piperazine-1-carboxylate (700 mg,1.91 mmol, 49% yield) was obtained as a white solid.

Step 2: 5-Methyl-7-piperazin-1-yl-pyrido[4,3-b]indole

To a solution of tert-butyl4-(5-methylpyrido[4,3-b]indol-7-yl)piperazine-1-carboxylate (700 mg,1.91 mmol, 1 eq) in dichloromethane (4 mL) was added hydrochloricacid/dioxane (4 M, 8 mL, 16.75 eq), then was stirred 25° C. for 1 h. TLC(dichloromethane/methanol=10/1) showed the starting material wasconsumed completely. The reaction mixture was concentrated to give aresidue. 5-Methyl-7-piperazin-1-yl-pyrido[4,3-b]indole (580 mg, crude,HCl) was obtained as a white solid without any purification.

Step 3

To a solution of 5-methyl-7-piperazin-1-yl-pyrido[4,3-b]indole (366 mg,1.21 mmol, 1 eq, HCl) and dimethyl4-[2-[2-[2-[2-[3-(p-tolylsulfonyloxy)propoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate(725 mg, 1.21 mmol, 1 eq) [prepared according to the scheme below andusing procedures described above and common procedures known to thoseskilled in the art]. in N,N-dimethylformamide (10 mL) was addedN,N-diisopropylethylamine (626 mg, 4.84 mmol, 0.8 mL, 4 eq), thenstirred at 80° C. for 16 h. The reaction mixture was concentrated togive a residue. The residue was purified by semi-preparative reversephase HPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 10%-40%, 30 min, 40% min). Dimethyl4-[2-[2-[2-[2-[3-[4-(5-methylpyrido[4,3-b]indol-7-yl)piperazin-1-yl]propoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate(131 mg, 0.19 mmol, 15% yield, 100% purity) was obtained as a brown oil.

Step 4:2-(2,6-dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperazin-1-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dione

Dimethyl4-[2-[2-[2-[2-[3-[4-(5-methylpyrido[4,3-b]indol-7-yl)piperazin-1-yl]propoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate(120 mg, 0.17 mmol, 1 eq), 3-aminopiperidine-2,6-dione (142 mg, 0.86mmol, 5 eq, HCl) and lithium iodide (347 mg, 2.60 mmol, 15 eq) weretaken up into a microwave tube in pyridine (4 mL). The sealed tube washeated at 120° C. for 2 h under microwave. The reaction mixture wasconcentrated to give a residue. The residue was purified bysemi-preparative reverse phase HPLC (8-38% acetonitrile+0.225% formicacid in water, over 10 min), then the collected fraction wasconcentrated to remove most of the acetonitrile and then lyophilized togive crude product. Then the crude product was purified by prep-TLC(dichloromethane/methanol=10/1), 10 mL water and 0.2 mL 1M hydrochloricacid was added and then lyophilized to give the product.2-(2,6-dioxopiperidin-3-yl)-5-((15-(4-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)piperazin-1-yl)-3,6,9,12-tetraoxapentadecyl)oxy)isoindoline-1,3-dionedihydrochloride (20 mg, 0.02 mmol, 14% yield) was obtained as anoff-white solid.

¹H NMR: (400 MHz, DMSO-d6) δ: 15.03 (br s, 1H), 11.18-10.95 (m, 2H),9.55 (s, 1H), 8.64 (br d, J=6.5 Hz, 1H), 8.30 (br d, J=8.3 Hz, 1H), 8.09(br d, J=6.9 Hz, 1H), 7.81 (br d, J=8.5 Hz, 1H), 7.48-7.23 (m, 4H), 5.11(br dd, J=5.0, 12.7 Hz, 1H), 4.30 (br s, 2H), 4.11 (br d, J=13.1 Hz,2H), 4.02 (s, 3H), 3.78 (br s, 2H), 3.70-3.48 (m, 18H), 3.19 (br s, 3H),2.96-2.82 (m, 1H), 2.62-2.55 (m, 3H), 2.04 (br s, 3H). (M+H)⁺ 757.6.

Synthetic Scheme for Exemplary Compound 211

2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(2-(6-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)ethoxy)propoxy)azetidin-1-yl)isoindoline-1,3-dione

Prepared according to the schemes below and using procedures describedabove and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 212

2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)but-2-yn-1-yl)oxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione

Step 1: tert-Butyl 3-(2-ethoxy-2-oxo-ethoxy)azetidine-1-carboxylate

To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (3 g, 17.32mmol, 1 eq) and diacetoxyrhodium (766 mg, 1.73 mmol, 0.1 eq) indichloromethane (50 mL) was added ethyl 2-diazoacetate (11.86 g, 103.92mmol, 6 eq) dropwise at 0° C. Then the reaction mixture was stirred at25° C. for 4 hours. TLC showed the starting material was not consumed.Then the reaction was stirred at 25° C. for another 16 hours. To thereaction solution was added acetic acid. Then the reaction was extractedwith dichloromethane (30 mL×3), and concentrated under vacuum to get theresidue. The residue was purified by silica gel column chromatography(Petroleum ether/Ethyl acetate=30/1 to 8:1) to get the product.tert-Butyl 3-(2-ethoxy-2-oxo-ethoxy)azetidine-1-carboxylate (2.24 g,8.64 mmol, 50% yield) was obtained as a light yellow oil.

Step 2: tert-Butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate

To a suspension of lithium aluminum hydride (229.51 mg, 6.05 mmol, 0.7eq) in tetrahydrofuran (30 mL) was added a solution of tert-butyl3-(2-ethoxy-2-oxo-ethoxy) azetidine-1-carboxylate (2.24 g, 8.64 mmol, 1eq) in tetrahydrofuran (10 mL) at −20° C. The reaction mixture wasstirred at 0° C. for 0.5 hour. The reaction solution was added water (20mL), the organic layer was extracted with ethyl acetate (40 mL×3). Thenthe combined organic phase was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified silica gel column chromatography (Petroleumether/Ethyl acetate=200/1 to 1:1) to get the product. tert-Butyl3-(2-hydroxyethoxy)azetidine-1-carboxylate (828 mg, 3.81 mmol, 44%yield) was obtained as a light yellow oil.

Step 3: 4-[(4-methoxyphenyl)methoxy]but-2-yn-1-ol

To a solution of but-2-yne-1,4-diol (5 g, 58.08 mmol, 1 eq) N,N-indimethyl formamide (50 mL) was added sodium hydride (2.32 g, 58.08 mmol,60% in mineral oil, 1 eq) at 0° C. The mixture was stirred at 0° C. for0.5 hour. Then methoxybenzylchloride (9.55 g, 60.98 mmol, 8.3 mL, 1.05eq) was added into the mixture at 0° C. slowly, the mixture was stirredat 25° C. for 4 hours. The reaction was added water (40 mL). Thesolution was extracted with ethyl acetate (40 mL×3). Then the combinedorganic phase was washed with brine (20 mL×2), dried with anhydroussodium sulfate, filtered and concentrated under vacuum to get theresidue. The residue was purified by silica gel column chromatography(Petroleum ether/Ethyl acetate=30/1 to 3:1) to get the product.4-[(4-methoxyphenyl)methoxy]but-2-yn-1-ol (2.64 g, 12.80 mmol, 22%yield) was obtained as a light yellow oil.

Step 4: 1-(4-bromobut-2-ynoxymethyl)-4-methoxybenzene

To a solution of 4-[(4-methoxyphenyl)methoxy]but-2-yn-1-ol (1 g, 4.85mmol, 1 eq) and perbromomethane (1.61 g, 4.85 mmol, 1 eq) indichloromethane (10 mL) was added triphenylphosphine (1.40 g, 5.33 mmol,1.1 eq) at 0° C. The solution was stirred at 25° C. for 16 hours. TLCshowed the starting material was consumed completely. The reactionsolution was concentrated under vacuum to get the residue. The residuewas purified by silica gel column chromatography (Petroleum ether/Ethylacetate=1/0 to 80:1) to get the product.1-(4-bromobut-2-ynoxymethyl)-4-methoxy-benzene (1 g, 3.72 mmol, 77%yield) was obtained as a light yellow oil.

The final compound, 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-((4-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)but-2-yn-1-yl)oxy)ethoxy)azetidin-1-yl)isoindoline-1,3-dione,was prepared according to the schemes below and using proceduresdescribed above and common procedures known to those skilled in the art.

Synthetic Scheme for Exemplary Compound 213

2-(2,6-dioxopiperidin-3-yl)-5-(6-(2-(2-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)ethoxy)ethoxy)-2-azaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione

Prepared according to the schemes below and using procedures describedabove and common procedures known to those skilled in the art.

Additional examples are being contemplated in the context of the currentinvention and are detailed below. They can be prepared as described inthe accompanying schemes, or by using procedures analogous to thosedescribed above (as indicated).

Synthetic Scheme for Compounds 215 and 217

Can be prepared according to the schemes below and using proceduresdescribed above and common procedures known to those skilled in the art.

Alternatively, one skilled in the art will recognize that differentsequence of steps and/or different protecting groups can be used in theassembly of the linkers of the examples described below. In addition,different sequence of attaching the linker to the PTM and ULM can beused for different examples, and sometimes different sequence of linkerassembly and PTM/ULM attachment can be used interchangeably for a givenexample (i.e., attach PTM first, then ULM, or attach ULM first, thenPTM). For example, linker for Compound 216 can be assembled as shown inthe scheme below.

Compound 216 can then be synthesized according to the scheme below.

Alternatively, Compound 216 can be synthesized using a differentsequence of PTM and ULM attachment according to the scheme below.

Synthetic Scheme for Exemplary Compound 4

4-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

¹H NMR (400 MHz, CDCl₃): δ 9.30 (s, 1H), 8.90 (br, 1H), 8.52 (d, J=5.6Hz, 1H), 8.42 (d, J=2.8 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.49 (dd,J=2.4, 8.8 Hz, 1H), 7.57 (s, 1H), 7.26-7.46 (m, 3H), 6.97 (d, J=7.2 Hz,1H), 6.81-6.87 (m, 2H), 6.35-6.46 (m, 1H), 4.89-4.98 (m, 1H), 4.54 (t,J=4.8 Hz, 2H), 3.90 (t, J=4.8 Hz, 2H), 3.61-3-74 (m, 15H), 3.37-3.81 (m,2H), 2.65-2.92 (m, 3H), 2.07-2.15 (m, 1H).

Using procedures described for Compound 4 the following were prepared:Compound 2, Compound 3, and Compound 48.

Synthetic Scheme for Exemplary Compound 7

(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

¹H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.71 (d, J=7.6 Hz, 1H), 7.70 (d,J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.34-7.42 (m, 5H), 7.22-7.23 (m,1H), 6.76 (d, J=7.6 Hz, 1H), 4.68 (s, 1H), 4.47-4.57 (m, 4H), 4.30-4.39(m, 1H), 4.05 (s, 3H), 3.56-4.87 (m, 23H), 2.64 (s, 4H), 2.45 (s, 3H),2.19 (br, 1H), 2.04 (br, 1H), 1.03 (s, 9H).

Using procedures described for Compound 7 the following were prepared:Compound 11, Compound 12, Compound 15, Compound 16, Compound 19,Compound 20, Compound 23, Compound 25, Compound 26.

Synthetic Scheme for Exemplary Compound 10

(2S,4R)-1-((S)-14-(4-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperazin-1-yl)-2-(tert-butyl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

¹H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.78 (d, J=7.6 Hz, 1H), 7.83 (d,J=7.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.35-7.40 (m, 6H), 7.23 (t, J=8.0Hz, 1H), 4.98-5.00 (m, 1H), 4.67 (s, 1H), 4.55-4.57 (m, 1H), 4.34-4.43(m, 3H), 3.83-4.03 (m, 7H), 3.72-3.74 (m, 16H), 2.46 (s, 3H), 2.17-2.21(m, 1H), 1.95-2.10 (m, 1H), 1.31 (d, J=8.8 Hz, 3H), 1.03 (s, 9H).

Using procedures described for compound 10 additional compounds wereprepared: 13, 14, 17, 18, 21, 22, 24, 41, 42.

Synthetic Scheme for Exemplary Compound 43

(2S,4R)-1-((2S)-2-(tert-butyl)-15-((2-(4-(dimethylamino)phenyl)quinolin-6-yl)oxy)-14-hydroxy-4-oxo-6,9,12-trioxa-3-azapentadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Prepared according to the schemes below using procedures described aboveand common procedures known to those skilled in the art.

¹HNMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 2.05-2.13 (m, 1H), 2.21-2.23 (m,1H), 2.46 (s, 3H), 3.05 (s, 6H), 3.65-3.74 (m, 10H), 3.79-3.90 (m, 2H),3.98-4.07 (m, 2H), 4.13-4.22 (m, 3H), 4.33-4.37 (m, 1H), 4.50-4.62 (m,3H), 4.70 (s, 1H), 6.89 (d, J=8.8 Hz, 2H), 7.25-7.26 (m, 1H), 7.38-7.44(m, 5H), 7.83 (d, J=8.8 Hz, 1H), 7.94-7.97 (m, 3H), 8.17 (d, J=8.8 Hz,1H), 8.85 (s, 1H).

Using procedures described for Compound 43 the following were prepared:Compound 45, Compound 46, Compound 47.

Synthetic Scheme for Exemplary Compound 8

(2S,4R)-1-((S)-2-(tert-butyl)-15-((2-(4-(dimethylamino)phenyl)quinolin-6-yl)oxy)-4-oxo-6,9,12-trioxa-3-azapentadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

¹HNMR (400 MHz, CD₃OD): δ 1.01, 1.03 (two singles, 9H), 2.07-2.25 (m,4H), 2.45, 2.47 (two singles, 3H), 3.04 (s, 6H), 3.65-3.71 (m, 10H),3.78-3.86 (m, 2H), 4.01-4.06 (m, 2H), 4.18-4.21 (m, 2H), 4.32-4.36 (m,1H), 4.50-4.60 (m, 3H), 4.68-4.70 (m, 1H), 6.88 (d, J=9.2 Hz, 2H),7.23-7.26 (m, 1H), 7.34-7.44 (m, 5H), 7.82 (d, J=8.4 Hz, 1H), 7.92-7.96(m, 3H), 8.16 (d, J=8.8 Hz, 1H), 8.85, 8.86 (two singles, 1H).

Using procedures described for Compound 8 the following were prepared:Compound 9, Compound 27, Compound 28, Compound 29, Compound 30, Compound31, Compound 32, Compound 33, Compound 34, Compound 35, Compound 36,Compound 37, Compound 38, Compound 39, Compound 40, Compound 44.

Synthetic Scheme of Exemplary Compound 49

3-(4-((14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Prepared according to the scheme below using procedures described aboveand common procedures known to those skilled in the art.

¹H NMR (400 MHz, CD₃OD): δ 9.36 (s, 1H), 8.39-8.45 (m, 3H), 8.30 (d,J=8.0 Hz, 1H), 8.01 (dd, J=2.4, 6.4 Hz, 1H), 7.78 (s, 1H), 7.70 (d,J=6.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.03 (d,J=7.6 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.12 (dd,J=5.2, 13.6 Hz, 1H), 4.47 (t, J=4.4 Hz, 2H), 4.27 (d, J=2.4 Hz, 2H),3.85 (d, J=4.4 Hz, 2H), 3.62-3.68 (m, 14H), 3.36 (t, J=5.6 Hz, 2H),2.75-2.95 (m, 2H), 2.35-2.47 (m, 1H), 2.10-2.21 (m, 1H).

Compound 218 can be prepared using procedures analogous to those ofCompound 195.

Compound 219 can be prepared using procedures analogous to those ofCompounds 73/180/112.

Compound 220 can be prepared using procedures analogous to those ofCompounds 73/173.

Compound 221 can be prepared using procedures analogous to those ofCompounds 111/127.

Compound 222 can be prepared using procedures analogous to those ofCompounds 141/180.

Compound 223 can be prepared using procedures analogous to those ofCompounds 102/180.

Compounds 224 and 225 can be prepared according to the schemes below.

Using approaches described above (including general approaches forCompounds 73, 173 and 180), Compound 226 through 234 can be prepared inanalogous ways by using common procedures known to those skilled in theart.

Additionally, combining these approaches with procedures described abovefor Compounds 138, 139, 140 and 203, Compound 235 through 240 can beprepared.

Compounds 241 through 247 can be prepared by using procedures analogousto those of Compounds 82/198 and 180.

Compounds 248 through 251 can be prepared based on the Compound 82followed by additional linker elaboration in a manner analogous toapproaches described above and known to those skilled in the art.

Compounds 252 through 256 can be prepared based on the approaches toCompounds 104, 99 and 198, and combination thereof.

Additional examples, Compounds 257 through 330, can be prepared based onthe fundamental PTM, ULM and linker approaches described above andcombined with applicable functional and protecting group elaborationsknown to those skilled in the art.

Exemplary PROTAC of the present disclosure can be prepared from the PTMembodiments of the present disclosure using the methods of linker and E3ligase-binding moiety attachment previously described.

Exemplary PROTAC of the present disclosure are represented by thestructures in Tables 1 and 2, while data associated with the exemplaryPROTACs is shown in Tables 2 and 3.

TABLE 1 Exemplary PROTAC of the present disclosure. Ex. Activ- #Structure (M + H)⁺ NMR data ity*  1

864.3 ¹HNMR (400 MHz, MeOD): δ 9.39 (s, 1H), 8.82 (s, 1H), 8.47-8.45 (m,2H), 8.33 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 6.4 Hz, 1H), 7.81 (s, 1H),7.73 (d, J = 6.0 Hz, 1H), 7.63 (d, J = 6.0 Hz, 1H), 7.43-7.36 (m, 4H),6.92 (d, J = 8.4 Hz, 1H), 4.78 (s, 1H), 4.69-4.50 (m, 5H), 4.43-4.31 (m,1H), 4.04-4.02 (m, 2H), 3.87- 3.85 (m, 3H), 3.73- 3.64 (m, 9H), 2.40 (s,3H), 2.25-2.19 (m, 1H), 2.15-2.10 (m, 1H), 1.03 (s, 9H). C  2

693.3 ¹H NMR (400 MHz, CDCl₃): δ 9.29 (s, 2H), 8.52-8.51 (m, 1H), 8.50(s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.54 (s,1H), 7.50-7.35 (m, 3H), 6.96 (d, J = 7.2 Hz, 1H), 6.83-6.81 (m, 2H),6.39 (s, 1H), 4.93-4.91 (m, 1H), 4.53 (s, 2H), 3.88 (s, 2H), 3.72-3.3.60(m, 10H), 3.40-3.30 (m, 2H), 2.88-2.70 (m, 3H), 2.15-2.10 (m, 1H). A  3

649.3 ¹H NMR (400 MHz, CDCl₃): δ 9.32 (s, 1H), 8.67 (s, 1H), 8.46-8.54(m, 2H), 8.15 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.58 (s,1H), 7.35-7.47 (m, 2H), 7.26 (s, 1H), 6.85-6.99 (m, 3H), 6.48 (s, 1H),4.92 (m, 1H), 4.56-4.58 (m, 2H), 3.93 (s, 2H), 3.41- 3.77 (m, 9H),2.71-2.85 (m, 3H), 2.02 (s, 1H). A  4

737.4 ¹H NMR (400 MHz, CDCl₃): δ 9.30 (s, 1H), 8.90 (br, 1H), 8.52 (d, J= 5.6 Hz, 1H), 8.42 (d, J = 2, 8 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.49(dd, J = 2.4, 8.8 Hz, 1H), 7.57 (s, 1H), 7.26-7, 46 (m, 3H), 6.97 (d, J= 7.2 Hz, 1H), 6.81-6.87 (m, 2H), 6.35-6.46 (m, 1H), 4.89- A 4.98 (m,1H), 4.54 (t, J = 4.8 Hz, 2H), 3.90 (t, J = 4.8 Hz, 2H), 3.61-3-74 (m,15H), 3.37-3.81 (m, 2H), 2.65-2.92 (m, 3H), 2.07-2.15 (m, 1H).  5

820.4 C  6

908.4 C  7

856.5 ¹H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H),7.70 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.34-7.42 (m, 5H),7.22- 7.23 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 4.68 (s, 1H), 4.47-4.57(m, 4H), 4.30-4.39 (m, 1H), 4.05 (s, 3H), 3.56-4.87 (m, 23H), 2.64 (s,4H), 2.45 (s, 3H), 2.19 (br, 1H), 2.04 (br, 1H), 1.03 (s, 9H). C  8

881.6 ¹HNMR (400 MHz, CD₃OD): δ 1.02 (s, 9H), 2.07-2.25 (m, 4H), 2.46(s, 3H), 3.04 (s, 6H), 3.65-3.71 (m, 10H), 3.78-3.86 (m, 2H), 4.01- 4.06(m, 2H), 4.18-4.21 (m, 2H), 4.32-4.36 (m, 1H), 4.50-4.60 (m, 3H),4.68-4.70 (m, 1H), 6.88 (d, J = 9.2 Hz, 2H), 7.23- 7.26 (m, 1H),7.34-7.44 (m, 5H), 7.82 (d, J = 8.4 Hz, 1H), 7.92-7.96 (m, 3H), 8.16 (d,J = 8.8 Hz, 1H), 8.86 (s, 1H). C  9

925.6 ¹HNMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 2.08-2.12 (m, 3H), 2.20-2.23 (m, 1H), 2.46 (s, 3H), 3.04 (s, 6H), 3.62- 3.71 (m, 14H), 3.78-3.89(m, 2H), 4.01-4.19 (m, 2H), 4.14-4.23 (m, 2H), 4.33-4.37 (m, 1H), 4.51-4.58 (m, 3H), 4.68-4.70 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 7.24 (br,1H), 7.36-7.45 (m, 5H), 7.62- 7.64 (m, 1H), 7.79-7.84 (m, 1H), 7.93-7.97(m, 3H), 8.17 (d, J = 8.0 Hz, 1H), 8.68 (s, 1H). C 10

870.5 ¹H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H),7.83 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.37-7.45 (m, 5H),7.25 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.68 (s, 1H),4.49-4.60 (m, 3H), 4.24-4.36 (m, 3H), 4.01-4.06 (m, 2H), 3.91- 3.98 (m,2H), 3.86-3.89 (m, 2H), 3.65-3.80 (m, 14H), 2.45 (s, 3H), 2.20- 2.26 (m,1H), 2.04-2.11 (m, 1H), 1.03 (s, 9H). C 11

840.6 ¹H NMR (400 MHz, MeOD): δ 8.70 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H),7.80 (d, J = 8.4 Hz, 1H), 7.53-7.55 (m, 3H), 7.43 (d, J = 8.4 Hz, 2H),7.37 (t, J = 8.0 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz,1H), 4.84 (s, 1H), 4.53-4.60 (m, 1H), 4.49 (s, 1H), 4.31- 4.35 (m, 1H),4.05 (s, 2H), 3.77-3.80 (m 5H), 3.65-3.70 (m, 10H), 2.64-2.66 (m, 6H),2.36 (s, 3H), 2.11-2.20 (m, 1H), 2.04-2.10 (m, 1H), 1.04 (s, 9H). C 12

884.4 ¹H NMR (400 MHz, MeOD): δ 8.71 (br, 1H), 8.12 (s, 1H), 7.80-7.82(m, 1H), 7.43-7.56 (m, 3H), 7.35-7.39 (m, 3H), 7.24-7.25 (m, 1H), 6.76-6.78 (m, 1H), 4.49 (s, 1H), 4.54-4.58 (m, 3H), 4.32-4.36 (m, 1H), 4.04(s, 1H), 3.81-3.92 (m, 5H), 3.61-3.69 (m, 12H), 3.35 (s 1H), 2.66-2.75(m, 6H), 2.37 (s, 3H), 2.20-2.22 (m, 1H), 2.07- 2.15 (m, 1H), 1.04 (s,9H). C 13

854.5 ¹H NMR (400 MHz, MeOD): δ 8.79 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H),7.85 (d, J = 8.0 Hz, 1H), 7.54-7.58 (m, 3H), 7.39- 7.43 (m, 2H), 7.28(t, J = 7.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.68 (s, 1H), 4.67 (s,1H), 4.55-4.61 (m, 1H), 4.44 (br, 1H), 4.29-4.35 (m, 5H), 3.80- 4.03 (m,8H), 3.71-3.82 (m, 13H), 3.37 (s, 3H), 2.20-2.22 (s, 1H), 2.08- 2.10 (m,1H), 1.04 (s, 9H). C 14

898.6 ¹H NMR (400 MHz, MeOD): δ 8.76 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H),7.84 (d, J = 7.2 Hz, 1H), 7.35-7.63 (m, 6H), 7.28 (t, J = 7.6 Hz, 1H),6.82 (d, J = 7.6 Hz, 1H), 4.68 (s, 1H), 4.50-4.61 (m, 3H), 4.28-4.39 (m,3H), 4.06 (s, 2H), 3.86-3.97 (m, 3H), 3.78-3.81 (m, 1H), 3.55-3.76 (m,16H), 3.18-3.23 (m, 2H), 2.35 (s, 3H), 2.21-2.26 (m, 1H), 2.04-2.10 (m,1H), 1.04 (s, 9H). C 15

870.6 ¹H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H),7.83 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.37-7.40 (m, 6H),7.26 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.99-5.01 (m, 1H),4.68 (s, 1H), 4.57 (t, J = 7.6 Hz, 1H), 4.44 (s, 1H), 4.05 (br, 2H),3.83-3.91 (m, 5H), 3.68-3.76 (m, 12H), 2.70 (m, 6H), 2.45 (s, 3H),2.17-2.20 (m, 1H), 1.96-2.05 (m, 1H), 1.56 (d, J = 7.2 Hz, 3H), 1.05 (s,9H). C 16

914.6 ¹H NMR (400 MHz, MeOD): δ 8.80-8.85 (m, 2H), 7.88 (d, J = 8.0 Hz,1H), 7.57 (d, J = 8.0 Hz, 1H), 7.32-7.46 (m, 7H), 6.93 (d, J = 8.0 Hz,1H), 4.99-5.01 (m, 1H), 4.68 (s, 1H), 4.55-4.57 (m, 1H), 4.43 (s, 1H),4.04 (s, 2H), 3.80-3.94 (m, 4H), 3.83-3.85 (m, 15H), 2.72-2.74 (m, 6H),2.46 (s, 3H), 2.12-2.13 (m, 1H), 1.97-1.99 (m, 1H), 1.96-2.05 (m, 1H),1.56 (d, J = 7.2 Hz, 3H), 1.05 (s, 9H). C 17

884.5 ¹H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.78 (d, J = 7.6 Hz, 1H),7.83 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.35-7.40 (m, 6H),7.23 (t, J = 8.0 Hz, 1H), 4.98- 5.00 (m, 1H), 4.67 (s, 1H), 4.55-4.57(m, 1H), 4.34-4.43 (m, 3H), 3.83- 4.03 (m, 7H), 3.72-3.74 (m, 16H), 2.46(s, 3H), 2.17-2.21 (m, 1H), 1.95- 2.10 (m, 1H), 1.31 (d, J = 8.8 Hz,3H), 1.03 (s, 9H). C 18

928.7 ¹H NMR (400 MHz, MeOD): δ 8.75-8.86 (m, 2H), 7.85 (d, J = 8.0 Hz,1H), 7.56 (d, J = 8.0 Hz, 1H), 7.34-7.42 (m, 5H), 7.27 (t, J = 7.6 Hz,1H), 6.79-6.85 (m, 1H), 4.94- 5.04 (m, 1H), 4.67 (s, 1H), 4.55-4.61 (m,1H), 4.44 (br, 1H), 4.29-4.35 (m, 2H), 4.07 (s, 2H), 3.83-3.96 (m, 4H),3.61- 3.79 (m, 16H), 3.18-3.23 (m, 2H), 2.45 (s, 3H), 2.18-2.23 (m, 1H),1.92- 1.99 (m, 1H), 1.48-1.57 (m, 3H), 1.03 (s, 9H). C 19

854.6 ¹H NMR (400 MHz, MeOD): δ 8.76 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H),7.84 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.4 Hz, 3H), 7.40 (d, J = 8.4 Hz,3H), 7.27 (t, J = 8.0 Hz, 1H), 6.85 (m, J = 7.6 Hz, 1H), 4.98-4.50 (m,1H), 4.75 (s, 1H), 4.57 (t, J = 7.6 Hz, 1H), 4.43 (s, 1H), 4.05 (s, 2H),3.83-3.91 (m, 5H), 3.67-3.76 (m, 12H), 2.70-2.71 (m, 6H), 2.37 (s, 3H),2.17-2.19 (m, 1H), 1.95-2.10 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H), 1.05 (s,9H). C 20

898.6 ¹H NMR (400 MHz, MeOD): δ 8.72 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H),7.81 (d, J = 8.0 Hz, 1H), 7.54-7.56 (m, 3H), 7.35-7.41 (m, 3H), 7.24 (t,J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.96-4.50 (m, 1H), 4.68 (s,1H), 4.55-4.59 (m, 1H), 4.43 (s, 1H), 4.04 (s, 2H), 3.74-3.89 (m, 5H),3.68-3.70 (m, 18H), 2.68-2.72 (m, 6H), 2.37 (s, 3H), 2.17-2.19 (m, 1H),1.95-2.10 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.04 (s, 9H). C 21

868.3 ¹H NMR (400 MHz, MeOD): δ 8.77 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H),7.82 (d, J = 8.0 Hz, 1H), 7.56-7.58 (m, 3H), 7.35- 7.41 (m, 3H), 7.23(d, J = 8.0 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.98-4.99 (m, 1H), 4.67(s, 1H), 4.55-4.59 (m, 1H), 4.43 (s, 1H), 4.33-4.35 (m, 2H), 3.86-4.01(m, 7H), 3.72-3.74 (m, 14H), 2.38 (s, 3H), 2.17-2.19 (m, 1H), 1.95-2.05(m, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.03 (s, 9H). C 22

912.6 ¹H NMR (400 MHz, MeOD): δ 8.75-8.81 (m, 1H), 8.06-8.10 (m, 1H),7.86 (d, J = 8.0 Hz, 1H), 7.55-7.61 (m, 3H), 7.35- 7.43 (m, 3H),7.25-7.31 (m, 1H), 6.81-6.88 (m, 1H), 4.94-5.04 (m, 1H), 4.67 (s, 1H),4.55-4.60 (m, 1H), 4.43 (br, 1H), 4.35 (s, 2H), 4.07 (s, 2H), 3.91-3.97(m, 3H), 3.82-3.85 (m, 1H), 3.61- 3.79 (m, 16H), 3.18-3.23 (m, 2H), 2.37(s, 3H), 2.18-2.23 (m, 1H), 1.92- 1.99 (m, 1H), 1.48-1.56 (m, 3H), 1.04(s, 9H). C 23

900.6 ¹H NMR (400 MHz, MeOD): δ 8.85 (s, 1H), 8.70 (d, J = 8.0 Hz, 1H),7.79 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.34-7.44 (m, 5H),7.24 (t, J = 6.8 Hz, 4.8 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 4.69 (s,1H), 4.57 (m, 3H), 4.50 (d, J = 4.8 Hz, 1H), 4.04 (s, 2H), 3.85 (s, 6H),3.60-3.69 (m, 15H), 2.66 (s, 6H), 2.65 (s, 3H), 2.08-2.45 (m, 2H), 2.28(s, 2H), 1.04 (s, 9H). C 24

914.6 1H NMR (400 MHz, MeOD): δ 8.84 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H),8.83 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.37-7.45 (m, 5H),7.24- 7.28 (m, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.86 (s, 1H), 4.50-4.63(m, 3H), 4.26-4.36 (m, 3H), 3.91- 4.03 (m, 4H), 3.86-3.89 (m, 2H),3.74-3.81 (m, 2H), 3.60-3.72 (m, 16H), 2.45 (s, 3H), 2.18-2.26 (m, 1H),2.05-2.11 (m, 1H), 1.03 (s, 9H). C 25

685.4 ¹H NMR (400 MHz, MeOD): δ 8.68 (d, J = 8.0 Hz, 1H), 7.80 (d, J =7.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.39-7.43 (m, 2H), 7.24 (m, J =7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 2H), 6.76 (d, J = 7.6 Hz, 1H), 4.74(m, 1H), 3.87 (br, 4H), 3.63-3.73 (m, 14H), 3.54 (s, 3H), 3.46-3.48 (m,2H), 3.37 C (s, 1H), 2.47 ( t, J = 6.8 Hz, 2H), 2.33 (t, J = 6.8 Hz,2H). 26

729.4 ¹H NMR (400 MHz, CD₃OD): δ 8.65 (d, J = 8.0 Hz, 1H), 7.77 (d, J =8.0 Hz, 1H ), 7.54 (d, J = 8.0 Hz, 1H), 7.35-7.43 (m, 2H), 7.24 (t, J =8.0 Hz, 1H), 6.95 (t, J = 8.8 Hz, 2H), 6.75 (d, J = 7.6 Hz, 1H), 5.03(dd, J = 4.2, 12.4 Hz, 1H), 4.58 (br, 4H), 3.70 (br, 4H), 3.60-3.70 (m,18H), 3.45-3.46 (m, 2H), 2.80- 2.85 (m, 1H), 2.66-2.75 (m, 2H),2.09-2.12 (m, 1H). C 27

823.7 ¹HNMR (400 MHz, CD₃OD): δ 1.02-1.05 (m, 9H), 2.07-2.13 (m, 1H),2.21-2.26 (m, 1H), 2.43- 2.47 (m, 3H), 3.05 (s, 6H), 3.76-3.83 (m, 5H),3.88-3.99 (m, 3H), 4.07- 4.12 (m, 2H), 4.30-4.35 (m, 3H), 4.47-4.52 (m,2H), 4.57-4.61 (m, 1H), 4.71-4.73 (m, 1H), 6.87- 6.90 (m, 2H), 7.24-7.29(m, 1H), 7.35-7.43 (m, 5H), 7.70-7.72 (m, 1H), 7.81-7.83 (m, 1H), 7.91-7.96 (m, 3H), 8.14-8.17 (m, 1H), 8.84 (s, 1H). C 28

837.7 ¹HNMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 1.42-1.58 (m, 3H), 1.94-2.01 (m, 1H), 2.17-2.23 (m, 1H), 2.46 (s, 3H), 3.04 (s, 6H), 3.75-3.85(m, 6H), 3.97-3.98 (m, 2H), 4.08-4.09 (m, 2H), 4.33-4.35 (m, 2H), 4.45(br, 1H), 4.56-4.60 (m, 1H), 4.70-4.72 (m, 1H), 4.94-4.97 (m, 1H), 6.87-6.90 (m, 2H), 7.30-7.43 (m, 6H), 7.68-7.71 (m, 1H), 7.84-7.86 (m, 1H),7.95-7.98 (m, 3H), 8.19- 8.21 (m, 1H), 8.45-8.47 (m, 1H), 8.86 (s, 1H).C 29

867.7 ¹H NMR (400 MHz, CD₃OD): δ 1.02 (s, 9H), 2.07-2.13 (m, 1H), 2.21-2.26 (m, 1H), 2.46 (s, 3H), 3.05 (s, 6H), 3.72- 3.77 (m, 9H), 3.87-3.92(m, 3H), 3.99-4.09 (m, 2H), 4.26-4.58 (m, 2H), 4.33-4.37 (m, 1H), 4.50-4.54 (m, 2H), 4.57-4.61 (m, 1H), 4.70-4.72 (m, 1H), 6.89 (d, J = 8.8 Hz,2H), 7.26 (d, J = 2.8 Hz, 1H), 7.37-7.45 (m, 5H), 7.66 (d, J = 9.6 Hz,1H), 7.85 (d, J = 8.4 Hz, 1H), 7.94-7.98 (m, 3H), 8.19 (d, J = 8.8 Hz,1H), 8.86 (s, 1H). C 30

881.4 ¹H NMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 1.46-1.53 (m, 3H), 1.96-2.04 (m, 1H), 2.19-2.21 (m, 1H), 2.49 (s, 3H), 3.05 (s, 6H), 3.73-3.81(m, 9H), 3.84-3.87 (m, 1H), 3.95-3.97 (m, 2H), 4.04-4.06 (m, 2H), 4.30-4.33 (m, 2H), 4.44-4.46 (m, 1H), 4.54-4.61 (m, 2H), 4.70 (s, 1H), 4.96-5.00 (m, 1H), 6.89 (m, 2H), 7.29-7.30 (m, 1H), 7.36-7.43 (m, 5H), 7.86(d, J = 8.8 Hz, 1H), 7.94- 7.98 (m, 3H), 8.20 (d, J = 8.8 Hz, 1H), 8.86(s, 1H). C 31

911.4 ¹H NMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 2.07-2.15 (m, 1H), 2.22-2.26 (m, 1H), 2.47 (s, 3H), 3.06 (s, 6H), 3.61- 3.75 (s, 12H), 3.82-3.83(m, 1H), 3.89-3.93 (m, 2H), 4.01-4.07 (m, 2H), 4.28-4.40 (m, 3H), 4.49-4.69 (m, 5H), 6.87-6.97 (m, 2H), 7.27-7.42 (m, 6H), 7.62-7.67 (br, 1H),7.83-7.98 (m, 4H), 8.17- 8.23 (m, 1H), 8.88 (s, 1H). C 32

925.4 ¹H NMR (400 MHz, CD₃OD): δ 1.06 (s, 9H), 1.50-1.58 (m, 3H), 1.94-2.03 (m, 1H), 2.17-2.25 (m, 1H), 2.48 (s, 3H), 3.06 (s, 6H), 3.70-3.77(m, 12H), 3.85-3.89 (s, 1H), 3.90-4.05 (m, 4H), 4.29-4.35 (m, 2H), 4.43-4.49 (m, 1H), 4.56-4.61 (m, 1H), 4.67-4.71 (m, 1H), 4.99-5.02 (m, 2H),6.88-6.91 (m, 2H), 7.30- 7.41 (m, 5H), 7.63-7.66 (m, 1H), 7.87-7.99 (m,4H), 8.19-8.23 (m, 1H), 8.50-8.52 (m, 1H), 8.87 (s, 1H). C 33

807.4 ¹H NMR (400 MHz, CD₃OD): δ 1.05 (s, 9H), 1.89-2.03 (m, 4H), 2.10-2 .14 (m, 1H), 2.22-2.26 (m, 1H), 2.46 (s, 3H), 3.05 (s, 6H), 3.67-3.70(m, 2H), 3.81-3.91 (m, 2H), 3.98-4.09 (m, 2H), 4.17-4.20 (m, 2H), 4.34-4.38 (m, 1H), 4.53-4.62 (m, 3H), 7.71-7.73 (m, 1H), 6.88-6.91 (m, 2H),7.24-7.28 (m, 1H), 7.34- 7.47 (m, 5H), 7.58-7.60 (m, 1H), 7.82-7.84 (m,1H), 7.91-7.97 (m, 3H), 8.15-8.17 (m, 1H), 8.83 (s, 1H). C 34

821.4 ¹H NMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 1.49-1.60 (m, 3H), 1.89-1.95 (m, 2H), 1.97-2.03 (m, 3H), 2.19-2.24 (m, 1H), 2.48 (s, 3H), 3.05(s, 6H), 3.69 (t, J = 6.0 Hz, 2H), 3.75-3.79 (m, 1H), 3.85-3.88 (m, 1H),3.99-4.09 (m, 2H), 4.19- 4.22 (m, 2H), 4.46 (br, 1H), 4.56-4.62 (m, 1H),4.70-4.73 (m, 1H), 4.98- 5.05 (m, 1H), 6.88-6.91 (m, 2H), 7.27-7.29 (m,1H), 7.38-7.44 (m, 5H), 7.57 (d, J = 9.6 Hz, 1H), 7.80-7.87 (m, 1H),7.94- 7.98 (m, 3H), 8.76-8.22 (m, 1H), 8.52 (d, J = 7.6 Hz, 1H), 8.86(s, 1H). C 35

851.4 ¹H NMR (400 MHz, CD₃OD): δ 1.03 (s, 9H), 1.91-1.92 (m, 2H), 2.05-2.26 (m, 4H), 2.45 (s, 3H), 3.04 (s, 6H), 3.62- 3.68 (m, 6H), 3.79-4.00(m, 4H), 4.15-4.25 (m, 2H), 4.33-4.36 (m, 1H), 4.50-4.61 (m, 3H), 4.69-4.71 (m, 1H), 6.88 (d, J = 8.0 Hz, 2H), 7.22-7.26 (m, 1H), 7.31-7.43 (m,4H), 7.54 (d, J = 8.4 Hz, 1H), 7.81-7.96 (m, 4H), 8.16 (d, J = 8.4 Hz,1H), 8.84, 8.86 (s, 1H). C 36

865.6 ¹H NMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 1.46-1.58 (m, 3H), 1.92-2.00 (m, 3H), 2.12-2.21 (m, 3H), 2.47 (s, 3H), 3.04 (s, 6H), 3.62-3.97(m, 10H), 4.23 (t, J = 5.2 Hz, 2H), 4.35-4.45 (m, 1H), 4.57-4.70 (m,2H), 4.98-5.01 (m, 1H), 6.88 (d, J = 8.4 Hz, 2H), 7.27- 7.56 (m, 7H),7.79-8.02 (m, 4H), 8.17-8.23 (m, 1H), 8.52 (d, J = 6.8 Hz, 1H), 8.87 (s,1H). C 37

821.4 ¹H NMR (400 MHz, CD₃OD): δ 1.03, 1.05 (two singles, 9H), 1.64-1.72 (m, 2H), 1.74-1.80 (m, 2H), 1.88-1.95 (m, 2H), 2.07-2.14 (m, 1H),2.22-2.27 (m, 1H), 2.43, 2.46 (two singles, 3H), 3.04 (s, 6H), 3.63 (t,J = 6.0 Hz, 2H), 3.80-3.83 (m, 1H), 3.88-3.91 (m, 1H), 3.96-4.05 (m,2H), 4.13 (t, J = 6.4 Hz, 2H), 4.32-4.34 (m, 1H), 4.48- 4.55 (m, 2H),4.58-4.63 (m, 1H), 4.69-4.74 (m, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.20 (s,1H), 7.33- 7.46 (m, 5H), 7.57 (d, J = 9.6 Hz, 1H), 7.81 (d, C J = 6.0Hz, 1H), 7.93 (t, J = 10.0 Hz, 3H), 8.14 (d, J = 8.8 Hz, 1H), 8.81 (s,1H). 38

835.4 ¹H NMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 1.44-1.58 (m, 3H), 1.66-1.81 (m, 4H), 1.89-2.02 (m, 3H), 2.14-2.31 (m, 1H), 2.46 (s, 3H), 3.05(s, 6H), 3.63 (t, J = 6.4 Hz, 2H), 3.74-3.78 (m, 1H), 3.85-3.88 (m, 1H),3.96-4.06 (m, 2H), 4.14- 4.19 (m, 2H), 4.37-4.46 (m, 1H), 4.56-4.62 (m,1H), 4.67-4.77 (m, 1H), 4.94-5.04 (m, 1H), 6.89 (d, J = 9.2 Hz, 2H),7.26 (t, J = 3.2 Hz, 1H), 7.35- 7.43 (m, 5H), 7.56 (d, J = 9.6 Hz, 1H),7.81-7.88 (m, 1H), 8.00-7.91 (m, 3H), 8.18 (d, J = 8.4 Hz, C 1H), 8.49(d, J = 7.2 Hz, 1H), 8.86 (s, 1H). 39

939.4 ¹H NMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 1.48-1.57 (m, 3H), 1.95-2.22 (m, 5H), 2.47 (s, 3H), 3.06 (s, 6H), 3.60- 3.66 (m, 12H), 3.70-3.86(m, 4H), 3.97-4.06 (m, 2H), 4.24 (t, J = 6.0 Hz, 2H), 4.44 (br, 1H),4.58 (t, J = 8.4 Hz, 1H), 4.68- 4.70 (m, 1H), 4.99-5.02 (m, 1H), 6.89(d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 7.37-7.43 (m, 5H), 7.61- 7.63 (m,1H), 7.84 (d, J = 8.4 Hz, 1H), 7.95-7.97 (m, 3H), 7.81-7.82 (m, 1H),8.86 (s, 1H). C 40

754.4 ¹HNMR (400 MHz, CD₃OD): δ 1.92-2.00 (m, 2H), 2.55-2.74 (m, 4H),2.93 (s, 6H), 3.28-3.37 (m, 4H), 3.46-3.53 (m, 12H), 3.60 (t, J = 6.2Hz, 2H), 4.11 (t, J = 6.2 Hz, 2H), 4.89-4.93 (m, 1H), 6.41-6.44 (m, 1H),6.76 (d, J = 8.8 Hz, 2H), 6.89 (t, J = 7.6 Hz, 2H), 7.13 (d, J = 2.4 Hz,1H), 7.23- 7.26 (m, 1H), 7.36-7.40 (m, 1H), 7.69 (d, J = 8.8 Hz, 1H),7.80-7.84 (m, 3H), 8.05 (d, J = 8.8 Hz, 1H). C 41

699.4 ¹H NMR (400 MHz, MeOD): δ 8.46 (d, J = 8.0 Hz, 1H), 7.64 (d, J =8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H),7.06-7.14 (m, 2H), 6.57-6.71 (m, 3H), 4.89-4.96 (m, 1H), 4.18 (s, 2H),3.84 (s, 2H), 3.46-3.70 (m, 16H), 3.30 (s, 2H), 2.58-2.76 (m, 3H),1.99-2.07 (m, 3H). C 42

743.7 ¹H NMR (400 MHz, MeOD): δ 8.65 (d, J = 8.0 Hz, 1H), 7.77 (d, J =8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.31-7.40 (m, 2H), 7.21-7.28 (m,1H), 6.84-7.90 (m, 2H), 6.76 (d, J = 8, 0 Hz, 1H), 5.00-5.04 (m, 1H),4.30 (s, 2H), 3.85-3.95 (m, 4H), 3.63-3.70 (m, 18H), 3.38 (s, 2H),2.61-2.90 (m, 3H), 2.02-2.21 (m, 1H). C 43

897.4 ¹H NMR (400 MHz, CD₃OD): δ 1.04 (s, 9H), 2.05-2.13 (m, 1H), 2.21-2.23 (m, 1H), 2.46 (s, 3H), 3.05 (s, 6H), 3.65- 3.74 (m, 10H), 3.79-3.90(m, 2H), 3.98-4.07 (m, 2H), 4.13-4.22 (m, 3H), 4.33-4.37 (m, 1H), 4.50-4.62 (m, 3H), 4.70 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 7.25-7.26 (m, 1H),7.38-7.44 (m, 5H), 7.83 (d, J = 8.8 Hz, 1H), 7.94- 7.97 (m, 3H), 8.17(d, J = 8.8 Hz, 1H), 8.85 (s, 1H). C 44

710.3 ¹HNMR (400 MHz, CDCl₃): δ 2.07-2.13 (m, 4H), 2.68-2.88 (m, 4H),3.04 (s, 6H), 3.33-3.45 (m, 2H), 3.64-3.69 (m, 11H), 4.16-4.18 (m, 2H),4.86-4.90 (m, 1H), 6.42- 6.44 (m, 1H), 6.81-6.85 (m, 3H), 7.06-7.07 (m,2H), 7.32 (d, J = 8.8 Hz, C 1H), 7.41-7.45 (m, 1H), 7.74-7.77 (m, 1H),7.98- 8.07 (m, 5H). 45

770.3 ¹H NMR (400 MHz, CDCl₃): δ 2.07-2.11 (m, 1H), 2.62-2.87 (m, 4H),3.04 (s, 6H), 3.40-3.43 (m, 2H), 3.65-3.78 (m, 16H), 4.13 (d, J = 5.2Hz, 2H), 4.24 (t, J = 4.2 Hz, 1H), 4.87-4.91 (m, 1H), 6.45-6.47 (m, 1H),6.81-6.87 (m, 3H), 7.06, 7.07 (two singles, 2H), 7.33-7.36 (m, 1H), 7.44(t, J = 7.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 8.01- 8.10 (m, 4H), 8.56(br. s, 1H). C 46

941.4 ¹HNMR (400 MHz, CD₃OD): δ 1.02, 1.04 (two singlets, 9H), 2.05-2.12 (m, 1H), 2.21-2.27 (m, 1H), 2.46, 2.47 (two singlets, 3H), 3.07 (s,6H), 3.63-3.70 (m, 14H), 3.79-3.90 (m, 2H), 3.98- 4.07 (m, 2H),4.13-4.24 (m, 3H), 4.33-4.37 (m, 1H), 4.50-4.61 (m, 3H), 4.69-4.71 (m,1H), 6.89 (d, J = 8.8 Hz, 2H), 7.33- 7.48 (m, 6H), 7.90 (d, J = 8.8 Hz,1H), 7.97-7.99 (m, 3H), 8.17 (d, J = 8.8 Hz, 1H), 8.87, 8.88 (twosinglets, 1H). C 47

726.3 1H NMR (400 Hz, CDCl₃): δ 2.01-2.24 (m, 2H), 2.68-2.88 (m, 3H),3.04 (s, 6H), 3.24 (s, 1H), 3.43 (s, 2H), 3.69 (s, 10 H), 4.15-4.24 (m,3H), 4.83-4.96 (m, 1H), 5.27-5.42 (m, 1H), 6.48 (s, 1H), 6.77-6.83 (m,3H), 7.07 (s, 2H), 7.34- 7.44 (m, 2H), 7.73-7.83 (m, 1H), 7.98-8.05 (m,4H), 8.27 (s, 1H). C 48

751.2 ¹H NMR (400 MHz, MeOD): δ 9.24 (s, 1H), 8.50 (d, J = 2.0 Hz 1H),8.45 (d, J = 5.6 Hz, 2H), 8.26 (d, J = 8.4 Hz, 1H), 8.06-8.09 (m, 1H),7.80 (s, 1H), 7.57 (t, J = 8.0 Hz, 2H), 7.44 (t, J = 8.4 Hz, 1H), 6.98(d, J = 8.4 Hz, 1H), 6.92-6.94 (m, 2H), 4.95-5.09 (m, 1H), 4.49-4.53 (m,2H), A 3.96 (s, 3H), 3.88 (d, J = 4.8 Hz, 2H), 3.63-3.70 (m, 14H), 3.41(t, J = 6.4 Hz, 2H), 2.64-2.82 (m, 3H). 49

723.3 ¹H NMR (400 MHz, CD₃OD): δ 9.36 (s, 1H), 8.39-8.45 (m, 3H), 8.30(d, J = 8.0 Hz, 1H), 8.01 (dd, J = 2.4, 6.4 Hz, 1H), 7.78 (s, 1H), 7.70(d, J = 6.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H),7.03 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.0 Hz,1H), 5.12 (dd, J = A 5.2, 13.6 Hz, 1H), 4.47 (t, J = 4.4 Hz, 2H), 4.27(d, J = 2.4 Hz, 2H), 3.85 (d, J = 4.4 Hz, 2H), 3.62- 3.68 (m, 14H), 3.36(t, J = 5.6 Hz, 2H), 2.75-2.95 (m, 2H), 2.35-2.47 (m, 1H), 2.10-2.21 (m,1H). 50

724.3 ¹H NMR (400 MHz, CDCl₃): δ 9.29 (s, 1H), 8.52 (s, 1H), 8.36 (s,1H), 8.13 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H),7.34- 7.43 (m, 4H), 6.99 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H),5.16-5.21 (m, 1H), 4.52 (s, 2H), 4.39-4.43 (m, 1H), 4.27- 4.31 (m, 1H),4.18 (d, J = A 3.2 Hz, 2H), 3.82-3.89 (m, 4H), 3.64-3.72 (m, 14H),2.85-2.89 (m, 1H), 2.72-2.81 (m, 1H), 2.27- 2.38 (m, 1H), 2.13-2.24 (m,1H). *Each compound was tested at 1000 nM, 300 nM and 100 nM asdescribed below. The highest amount of degradation observed at anydosage for each compound is capture in Table 1 as follows: A: ≤50% tauprotein remaining after 72 hours of incubation with the test compound;B: ≤80% and >50% tau protein remaining after 72 hours of incubation withthe test compound; C: >80% tau protein remaining after 72 hours ofincubation with the test compound.

TABLE 2 Exemplary PROTAC of the present disclosure. MH+ Degra- (1)dation [MH+ Ex. activ- (2), if # Structure ity* isotope] NMR transcript51

A 738.3 ¹H NMR (400 MHz, CDCl₃): δ 12.34-12.48 (m, 1H), 9.19-9.29 (m,1H), 8.80 (s, 1H), 8.29- 8.42 (m, 1H), 8.02-8.14 (m, 1H), 7.95 (s, 1H),7.69- 7.81 (m, 1H), 7.60 (s, 2H), 7.17 (s, 1H), 7.09 (s, 1H), 6.62 (s,1H), 4.97 (s, 1H), 4.43 (s, 2H), 4.14 (s, 2H), 3.88 (d, J = 24.1 Hz,3H), 3.78 (d, J = 8.2 Hz, 3H), 3.69 (d, J = 10.0 Hz, 6H), 2.80 (m, 4H),1.99- 2.29 (m, 4H). 52

C 758.3 ¹HNMR (400 MHz, MeOD): δ 9.25 (s, 1H), 8.79 (s, 1H), 8.37-8.39(d, J = 8 Hz, 1H), 8.28-8.30 (d, J = 8 Hz, 1H), 8.11-8.13 (d, J = 8 Hz,1H), 7.80 (s, 1H), 7.75-7.77 (d, J = 8 Hz, 1H), 7.60 (s, 1H), 7.49-7.51(d, J = 8 Hz, 1H), 7.43-7.45 (d, J = 8 Hz, 1H), 7.33 (s, 1H), 5.07-5.09(m, 1H), 4.06- 4.09 (m, 2H), 3.57-3.60 (m, 2H), 3.51-3.54 (m, 2H),2.93-2.95 (m, 2H), 2.91-2.93 (m, 1H), 2.59- 2.75 (m, 12H), 2.37-2.41 (m,2H), 2.04-2.06 (m, 3H), 1.78-1.80 (m, 2H), 1.46-1.55 (m, 5H). 53

C 714.3 ¹H NMR (400 MHz, CDCl₃): δ 9.34 (s, 1H), 8.55 (d, J = 5.6 Hz,1H), 8.44 (m, 2H), 8.20 (d, J = 8.4 Hz, 1H), 7.87-7.92 (m, 3H), 7.68 (d,J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.48- 7.50 (m, 1H), 7.38 (d, J = 5.6 Hz,1H), 7.06 (m, 1H), 6.84 (d, J = 8.8 Hz, 2H), 4.93-4.94 (m, 2H), 3.75 (m,2H), 3.42-3.49 (m, 6H), 2.72-2.98 (m, 5H), 2.61 (s, 4H), 2.53 (t, J =7.2 Hz, 2H), 2.15-2.18 (m, 2H), 1.81 (t, J = 6.8 5Hz, 2H). 54

C 714.3 ¹H NMR (400 MHz, CD₃OD): δ 9.31 (s, 1H), 8.83 (s, 1H), 8.42 (d,J = 6.1 Hz, 2H), 8.34 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H),7.84 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 16.5, 6.4 Hz, 2H),7.47 (d, J = 8.3 Hz, 1H), 7.36 (s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 5.06-5.13 (m, 1H), 4.14 (s, 2H), 2.83 (m, 18H), 2.04 (s, 3H), 1.87 (s, 2H),1.69 (s, 2H), 1.55 (s, 2H). 55

C 763.3 ¹H NMR (400 MHz, MeOD): δ 9.62 (s, 1H), 9.03 (s, 1H), 8.58 (d, J= 6.8 Hz, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.31-8.40 (m, 1H), 8.08 (s,1H), 7.87- 7.99 (m, 2H), 7.78-7.87 (m, 3H), 7.68-7.72 (m, 1H), 7.26-7.30(m, 2H), 7.10-7.14 (m, 1H), 5.08- 5.12 (m, 1H), 4.17 (t, J = 6.0 Hz,2H), 3.81-3.92 (m, 4H), 3.50-3.60 (m, 4H), 3.30-3.40 (m, 2H), 3.10- 3.18(m, 2H), 2.71-2.86 (m, 5H), 2.30-2.33 (m, 2H), 2.10-2.16 (m, 3H). 56

C 786.3 ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H), 8.89 (s, 1H), 8.53 (s,1H), 8.42 (s, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 6.2 Hz, 1H),7.77 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.42(s, 1H), 7.29 (d, J = 11.5 Hz, 1H), 7.17 (d, J = 6.5 Hz, 1H), 6.82 (d, J= 8.2 Hz, 1H), 5.34 (s, 2H), 5.00-4.87 (m, 1H), 4.07 (s, 2H), 3.75 (s,1H), 3.57 (s, 1H), 3.04-2.49 (m, 10H), 2.20 (m, 4H), 2.01 (s, 4H), 1.85(s, 3H), 1.75- 1.55 (m, 3H), 1.52 (s, 2H). 57

C 728.3 ¹H NMR (400 MHz, CD₃OD): δ 9.30 (s, 1H), 8.42-8.60 (m, 2H), 8.19(d, J = 8.0 Hz, 1H), 7.60-7.65 (m, 2H), 7.52 (s, 1H), 7.31 (d, J = 8.0Hz, 1H), 7.19 (s, 1H), 7.12-7.14 (m, 1H), 5.07-5.10 (m, 1H), 4.12 (t, J= 4.0 Hz, 2H), 3.66-3.86 (m, 18H), 3.37 (s, 2H), 3.15-3.20 (m, 3H),2.71- 2.76 (m, 3H), 2.09-2.22 (m, 5H). 58

C 758.3 ¹H NMR (400 MHz, CD₃OD): δ 9.25 (s, 1H), 8.79 (s, 1H), 8.39 (d,J = 6.0 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H),7.79 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52(d, J = 5.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 6.0 Hz, 1H),5.07-5.09 (m, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 5.2 Hz, 2H),3.47 (t, J = 6.0 Hz, 2H), 2.47-2.88 (m, 16H), 1.98-2.1 (m, 4H),1.80-1.84 (m, 2H), 1.55- 1.57 (m, 5H). 59

C 786.3 ¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 11.11 (s, 1H), 9.35(s, 1H), 8.55 (s, 1H), 8.42 (d, J = 5.4 Hz, 1H), 8.29 (d, J = 8.2 Hz,1H), 8.17 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H),7.76 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.42(s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 5.31 (s,1H), 5.11 (dd, J = 12.9, 5.2 Hz, 1H), 4.17 (d, J = 6.7 Hz, 3H), 3.42 (d,J = 5.4 Hz, 2H), 2.96-2.78 (m, 2H), 2.60 (dd, J = 34.5, 18.5 Hz, 2H),2.37 (dd, J = 44.1, 5.8 Hz, 13H), 2.01 (d, J = 14.9 Hz, 2H), 1.76 (s,2H), 1.41 (dd, J = 43.8, 29.4 Hz, 4H), 1.23 (s, 2H). 60

C 714.3 ¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 9.76 (s, 1H), 8.67(d, J = 6.0 Hz, 1H), 8.60 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.16 (d, J= 8.4 Hz, 1H), 8.80-8.02 (m, 2H), 7.77 (t, J = 8.4 Hz, 2H), 7.50 (s,1H), 7.37 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 5.36 (m, 1H),5.07-5.11 (m, 1H), 4.24 (br, 3H), 3.62 (br, 9H), 3.55 (s, 3H), 3.17-3.25(m, 6H), 2.86-2.93 (m, 1H), 2.38-2.62 (m, 4H), 1.97-2.04 (m, 1H). 61

C 796.3 ¹H NMR (400 MHz, CD₃OD) δ 9.35 (s, 1H), 8.89 (s, 1H), 8.55 (d, J= 5.8 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.17-8.22 (m, 1H), 8.05 (s,1H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.51 (d, J =8.2 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 5.40 (d, J = 9.1 Hz, 2H), 5.08-5.16 (m, 1H), 4.95 (s, 4H), 4.59 (s, 2H), 4.18 (t, J = 6.2 Hz, 1H),2.91-3.00 (m, 2H), 2.58-2.91 (m, 9H), 2.12-2.18 (m, 1H), 2.06 (s, 2H),1.89 (s, 2H), 1.69 (s, 2H), 1.57 (s, 2H). 62

C 714.3 ¹HNMR (400 MHz, MeOD): δ 9.27 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H),8.46 (d, J = 6.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 2.4 Hz,1H), 7.90 (s, 1H), 7.59-7.70 (m, 3H), 7.47 (d, J = 6.0 Hz, 1H),7.03-7.09 (m, 2H), 5.06-5.12 (m, 1H), 4.42 (d, J = 5.6 Hz, 2H), 4.07 (t,J = 6.4 Hz, 2H), 3.99 (s, 3H), 2.89-2.96 (m, 3H), 2.51-2.75 (m, 13H),2.12- 2.24 (m, 1H), 2.01-2.03 (m, 3H), 1.82-1.84 (m, 2H), 1.52-1.63 (m,6H). 63

C 796.2 ¹H NMR (400 MHz, CD₃OD): δ 9.25 (s, 1H), 8.45 (s, 1H), 8.23 (d,J = 7.6 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.59 (d, J =8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.35 (s, 2H), 7.26-7.28 (m, 1H),6.06 (s, 1H), 5.72 (s, 1H), 5.06-5.08 (m, 1H), 4.30 (d, J = 6.4 Hz, 1H),4.11-4.15 (m, 2H), 3.90- 3.94 (m, 4H), 3.70-3.74 (m, 2H), 3.03-3.06 (m,2H), 2.82-2.88 (m, 4H), 2.71-2.75 (m, 6H), 2.51- 2.55 (m, 3H), 2.05-2.25(m, 2H), 1.82-1.86 (m, 2H), 1.61-1.63 (m, 2H), 1.51-1.52 (m, 2H). 64

C 791.2 ¹H NMR (400 MHz, CD₃OD) δ 9.42 (s, 1H), 8.53 (d, J = 2.3 Hz,1H), 8.50 (d, J = 6.1 Hz, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.13 (d, J =8.0 Hz, 2H), 7.87 (s, 1H), 7.71-7.78 (m, 2H), 7.68 (d, J = 8.3 Hz, 1H),7.42 (s, 1H), 7.33 (s, 2H), 7.29 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.6Hz, 1H), 5.51 (s, 2H), 5.06- 5.14 (m, 2H), 3.55 (s, 4H), 2.58-3.03 (m,15H), 2.04 (m, 3H). 65

C 757.5 ¹H NMR: (400 MHz, DMSO-d6) δ: 11.80 (s, 1H), 11.11 (s, 1H), 9.35(s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.29 (d, J= 8.4 Hz, 1H), 8.18 (s, 3H), 8.11 (dd, J = 2.4, 8.8 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.76 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 5.6Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 2.0, 8.4 Hz, 1H), 6.92(d, J = 8.4 Hz, 1H), 5.30 (d, J = 3.6 Hz, 1H), 5.11 (dd, J = 5.6, 13.2Hz, 1H), 4.35 (t, J = 6.4 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 2.93-2.84(m, 2H), 2.77 (s, 2H), 2.63- 2.54 (m, 3H), 2.37 (d, J = 6.0 Hz, 4H),2.22-1.98 (m, 4H), 1.87-1.74 (m, 4H), 1.53-1.38 (m, 6H). 66

C 783.6 ¹H NMR (400 MHz, DMSO-d₆): δ 13.21 (s, 1H), 11.08 (s, 2H), 9.76(s, 1H), 8.67 (d, J = 6.6 Hz, 1H), 8.61 (s, 1H), 8.52 (d, J = 8.3 Hz,1H), 8.17 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 7.1 Hz, 2H), 7.82-7.72 (m,3H), 7.46 (s, 2H), 7.35 (s, 2H), 6.96 (d, J = 8.5 Hz, 1H), 5.34 (s, 1H),5.08 (d, J = 7.7 Hz, 2H), 4.40 (s, 2H), 3.23 (s, 4H), 3.15 (s, 4H), 3.02(s, 4H), 2.95- 2.83 (m, 4H), 2.59 (d, J = 15.7 Hz, 4H), 2.44 (s, 2H),2.01 (s, 5H), 1.77 (d, J = 14.7 Hz, 2H). 67

A 820.5 ¹H NMR (400 MHz, CD₃OD): δ 9.25 (s, 1H), 8.79 (s, 1H), 8.37-8.39(d, J = 8.0 Hz, 1H), 8.28-8.30 (d, J = 8.0 Hz, 2H), 7.89 (s, 1H),7.63-7.65 (d, J = 8.0 Hz, 1H), 7.54-7.56 (m, 2H), 7.26 (s, 1H), 7.18-7.20 (m, 1H), 5.02-5.05 (m, 1H), 4.62-4.64 (m, 2H), 4.17-4.19 (m, 2H),3.95 (s, 3H), 3.88-3.90 (m, 2H), 3.82-3.84 (m, 2H), 3.61-3.71 (m, 13H),2.55- 2.81 (m, 3H), 2.95-2.99 (m, 1H). 68

C 756.6 ¹H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 9.37 (s, 1H), 8.64(s, 1H), 8.50 (d, J = 4.0 Hz, 1H), 8.33 (d, J = 12.0 Hz, 1H), 8.00 (s,1H), 7.68-7.60 (m, 3H), 7.34 (d, J = 4.0 Hz, 1H), 7.25 (dd, J = 8.0 Hz,4.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.32 (t, J = 4.0 Hz, 1H), 5.07(dd, J = 12.0 Hz, 8.0 Hz, 1H), 4.20-4.17 (m, 1H), 3.96 (s, 3H), 4.46 (s,6H), 2.88-2.84 (m, 1H), 2.59-2.54 (m, 7H), 2.43- 2.32 (m, 6H), 2.02-1.98(m, 1H), 1.57-1.49 (m, 4H), 1.38-1.34 (m, 2H). 69

A 820.5 ¹H NMR (400 MHz, CD₃OD): δ 9.21 (s, 1H), 8.79 (s, 1H), 8.38 (d,J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.46-7.49 (m, 2H), 7.26 (s,1H), 7.15- 7.19 (m, 2H), 7.07 (s, 1H), 4.95-4.99 (m, 1H), 4.45- 4.47 (m,2H), 4.15-4.18 (m, 2H), 3.77-3.82 (m, 7H), 3.54-3.62 (m, 9H), 2.45-2.77(m, 3H), 1.91- 1.95 (m, 1H), 1.12-1.16 (m, 1H). 70

A 778.5 ¹H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 9.36 (s, 1H), 8.62(s, 1H), 8.50 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.8 Hz,1H), 7.97 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H),7.43 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 5.31(s, 1H), 5.11 (dd, J = 12.8, 5.1 Hz, 1H), 4.31 (s, 2H), 4.22 (s, 1H),3.95 (s, 3H), 3.79 (s, 2H), 3.64-3.48 (m, 10H), 3.45 (d, J = 4.9 Hz,3H), 2.86 (d, J = 13.2 Hz, 1H), 2.45-2.40 (m, 2H), 2.37-2.30 (m, 2H),2.02 (d, J = 6.5 Hz, 1H). 71

A 746.5 ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.38 (d, J = 8.4 Hz,1H), 8.30 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 3.0 Hz, 1H), 8.11 (s, 1 H),7.80 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.63-7.68 (m, 2H),7.44 (d, J = 2.0 Hz, 1H), 7.34-7.36 (m, 1H), 5.08-5.12 (m, 1H), 4.48 (s,2H), 4.31 (t, J = 3.6 Hz, 2H), 3.98 (s, 3H), 3.80 (s, 3H), 3.53-3.79 (m,12H), 1.95-2.08 (m, 2H). 72

C 792.5 ¹H NMR (400 MHz, CD₃OD): δ 13.19 (s, 1H), 9.77 (s, 1H),8.62-8.68 (m, 2H), 8.52 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H), 8.01- 8.02(m, 2H), 7.80-7.81 (m, 1H), 7.15-7.28 (m, 1H), 6.99 (d, J = 8.0 Hz, 1H),5.15-5.23 (m, 1H), 4.43-4.45 (m, 2H), 3.77- 3.89 (m, 4H), 3.49-3.60 (m,12H), 2.86-3.05 (m, 3H), 1.99-2.01 (m, 1H). 73

A 719.4 ¹H NMR (400 MHz, DMSOd-6): δ 2.04-2.07 (m, 1H), 2.57-2.77 (m,6H), 2.86-2.93 (m, 1H), 5.10-5.14 (m, 2H), 5.32 (s, 2H), 5.39-5.48 (m,1H), 6.97 (d, J = 8.0 Hz, 1H), 7.32-7.33 (m, 1H), 7.46- 7.58 (m, 5H),7.77 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 8.25(s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 8.56 (s, 1H), 9.36 (s,1H), 11.12 (s, 1H), 11.82 (s, 1H). 74

A 750.5 ¹H NMR (400 MHz, CDCl₃): δ 9.65 (s, 1H), 9.22 (s, 1H), 8.67-8.73(m, 2H), 8.47 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.59- 7.71 (m, 2H), 7.04 (d, J = 9.2 Hz,2H), 4.93-4.96 (m, 1H), 4.10 (s, 5H), 3.87 (s, 1H), 3.55-3.76 (m, 18H),3.26 (s, 2H), 2.12-2.16 (m, 2H). 75

C 771.6 ¹H NMR (400 MHz, DMSO-d₆) δ = 11.07 (s, 1H), 9.38- 9.32 (m, 1H),8.66-8.63 (d, J = 12 Hz 1H), 8.50- 8.48 (m, J = 8 Hz 1H), 8.36 (s, 2H),8.34-8.29 (m, 1H), 8.21-8.14 (m, 1H), 7.99-7.94 (m, 1H), 7.61 (s, 3H),7.28-7.22 (m, 1H), 7.19-7.12 (m, 1H), 6.96-6.89 (m, 1H), 5.09-5.00 (m,1H), 4.36- 4.29 (m, 2H), 3.95 (s, 5H), 3.34 (s, 4H), 2.87 (s, 2H),2.99-2.78 (m, 1H), 2.82- 2.73 (m, 1H), 2.04-1.93 (m, 1H), 1.82-1.65 (m,4H), 1.61-1.52 (m, 2H), 1.52-1.41 (m, 5H), 1.28 (s, 4H), 1.22-1.05 (m,4H). 76

C 751.5 ¹H NMR (400 MHz, CD₃OD): δ 9.32 (s, 1H), 8.96 (s, 1H), 8.45-8.52(m, 2H), 8.37 (d, J = 8.0 Hz, 1H), 8.27-8.31 (m, 1H), 7.98 (s, 1H),7.61-7.98 (m, 4H), 6.82 (s, 1H), 6.65- 6.67 (m, 1H), 5.01-5.05 (m, 1H),4.59 (m, 1H), 4.27 (t, J = 8.4 Hz, 1H), 4.02 (s, 3H), 3.88-3.91 (m, 2H),3.70 (s, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.41 (m, 1H), 3.13-3.17 (m, 2H),2.66-2.86 (m, 11H), 2.02- 2.03 (m, 3H). 77

C 723.5 ¹H NMR (400 MHz, CD₃OD): δ 9.56 (s, 1H), 8.54-8.56 (m, 2H), 8.45(d, J = 8.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H),7.97 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz,1H), 7.79 (s, 1H), 7.76-7.78 (d, J = 8 Hz, 1H), 7.29 (s, 1H), 7.21 (d, J= 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.48-5.52 (m, 1H), 5.32- 5.34(m, 1H), 5.18-5.22 (m, 1H), 5.06-5.10 (m, 1H), 4.25-4.28 (m, 2H),3.21-3.23 (m, 3H), 2.78- 2.81 (m, 5H), 2.67-2.70 (m, 2H), 2.30-2.33 (m,2H), 2.17-2.19 (m, 1H), 1.97-2.07 (m, 3H). 78

C 770.6 ¹H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.35 (s, 1H), 8.64(t, J = 3.9 Hz, 1H), 8.49 (d, J = 4.7 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H),8.19 (dd, J = 8.6, 2.5 Hz, 1H), 7.98 (s, 1H), 7.68-7.48 (m, 3H), 7.31(d, J = 7.8 Hz, 1H), 7.20 (t, J = 9.5 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H),5.07 (dd, J = 12.9, 5.3 Hz, 1H), 4.33 (t, J = 6.5 Hz, 2H), 3.95 (s, 3H),3.65 (m, 1H), 3.51-3.41 (m, 3H), 3.36-3.23 (m, 5H), 2.95- 2.83 (m, 1H),2.43-2.28 (m, 6H), 2.05-1.96 (m, 1H), 1.79-1.73 (m, 1H), 1.67-1.61 (m,1H), 1.42 (m, 7H). 79

A 759.6 ¹H NMR (400 MHz, CDCl₃): δ 9.35 (s, 1H), 8.59 (d, J = 5.7 Hz,1H), 8.49 (s, 1H), 8.28 (s, 1H), 8.21 (d, J = 10.6 Hz, 1H), 8.00 (s,1H), 7.91 (d, J = 11.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.57 (s, 1H),7.51 (d, J = 9.3 Hz, 1H), 7.37 (d, J = 5.9 Hz, 1H), 6.85 (d, J = 8.6 Hz,1H), 6.77 (s, 1H), 4.92 (m, 1H), 4.45 (s, 1H), 4.36 (t, J = 6.6 Hz, 2H),4.16-4.26 (m, 2H), 3.83-3.98 (m, 4H), 3.44 (m, 4H), 2.63-2.92 (m, 3H),2.11 (d, J = 6.4 Hz, 2H), 1.79-1.89 (m, 3H), 1.44-1.70 (m, 10H). 80

A 759.6 ¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (s, 1H), 9.35 (s, 1H), 8.63(d, J = 2.3 Hz, 1H), 8.50 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.18 (dd, J= 8.6, 2.5 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.60 (d, J =6.8 Hz, 2H), 7.23 (d, J = 7.2 Hz, 2H), 6.93 (d, J = 8.6 Hz, 1H), 5.10(m, 1H), 5.02-4.95 (m, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.95 (s, 3H), 3.70(t, J = 6.8 Hz, 2H), 2.99-2.95 (m, 2H), 2.86 (d, J = 12.1 Hz, 2H), 2.64(br, 1H), 2.55 (br, 2H), 2.33 (s, 2H), 2.06-1.96 (m, 3H), 1.81- 1.70 (m,3H), 1.60-1.40 (m, 8H). 81

A 756.5 ¹H NMR (400 MHz, CDCl₃): δ 9.31 (s, 1H), 8.51 (s, 1H), 8.40 (s,1H), 8.11 (d, J = 8.0 Hz, 1H), 7.82-7.83 (m, 1H), 7.60 (s, 1H),7.37-7.45 (m, 3H), 6.84 (d, J = 8.0 Hz, 1H), 4.92-4.95 (m, 1H), 4.53 (t,J = 4.8 Hz, 2H), 4.24 (t, J = 4.8 Hz, 2H), 3.89-3.91 (m, 4H), 3.67- 3.75(m, 12H), 2.74-2.92 (m, 3H), 2.12-2.16 (m, 1H). 82

C 771.6 ¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (s, 1H), 9.36 (s, 1H), 8.64(d, J = 2.2 Hz, 1H), 8.50 (d, J = 5.7 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H),8.19 (dd, J = 8.8, 2.6 Hz, 2H), 7.98 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H),7.62 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz,1H), 6.94 (d, J = 8.7 Hz, 1H), 5.31 (s, 1H), 5.12 (dd, J = 12.9, 5.3 Hz,1H), 4.40- 4.32 (m, 1H), 4.18 (t, J = 6.4 Hz, 2H), 3.96 (s, 3H), 2.88(d, J = 13.2 Hz, 2H), 2.74 (s, 2H), 2.36 (m, 6H), 2.07 (s, 3H),1.88-1.70 (m, 4H), 1.60-1.34 (m, 6H). 83

C 751.5 ¹H NMR (400 MHz, CD₃OD): δ 9.58 (s, 1H), 8.58 (d, J = 6.4 Hz,1H), 8.54-8.55 (d, J = 4 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.39 (d, J =2.8 Hz, 1H), 8.12-8.17 (m, 2H), 7.97-8.01 (m, 2H), 7.91 (d, J = 9.2 Hz,1H), 7.79- 7.83 (m, 2H), 7.39 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.01(d, J = 8.4 Hz, 1H), 5.50-5.53 (m, 1H), 5.22- 5.24 (m, 1H), 5.12-5.14(m, 1H), 4.18-4.21 (m, 2H), 3.04-3.07 (m, 2H), 2.74-2.84 (m, 7H), 2.18-2.20 (m, 1H), 2.09-2.13 (m, 1H), 2.02-2.06 (m, 1H), 1.85-1.95 (m, 4H),1.55-1.65 (m, 4H). 84

C 794.5 1H NMR (400 MHz, CDCl₃): δ 9.34 (s, 1H), 8.58 (d, J = 5.6 Hz,1H), 8.21-8.48 (m, 2H), 8.20 (d, J = 8.4 Hz, 1H), 7.88-7.91 (m, 1H),7.76 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.33-7.36 (m, 2H), 7.16-7.18 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.39-6.51 (m,3H), 5.52-5.54 (m, 1H), 4.94-4.96 (m, 2H), 4.07- 4.10 (m, 2H), 3.91-3.97(m, 5H), 3.22-3.24 (m, 1H), 2.69-2.76 (m, 7H), 2.14-2.16 (m, 1H), 1.82-1.86 (m, 4H), 1.54-1.57 (m, 4H). 85

A 774.6 ¹H NMR (400 MHz, CDCl₃): δ 9.32 (s, 1H), 8.58-8.59 (d, J = 4.0Hz, 2H), 8.48 (s, 1H), 8.16- 8.18 (d, J = 8.0 Hz, 1H), 7.89-7.91 (d, J =8.0 Hz, 1H), 7.74-7.76 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.47-7.49 (d,J = 8.0 Hz, 1H), 7.32-7.33 (d, J = 4.0 Hz, 1H), 7.19 (s, 1H), 7.06-7.08(d, J = 8.0 Hz, 1H), 6.84-6.86 (d, J = 8.0 Hz, 1H), 4.93 (m, 2H),4.35-4.38 (m, 2H), 4.21 (s, 1H), 3.90 (s, 3H), 3.35- 3.49 (m, 7H),2.68-2.95 (m, 3H), 2.44-2.51 (m, 4H), 2.15 (m, 1H), 1.88 (m, 2H),1.56-1.68 (m, 9H), 1.44 (d, J = 8.0 Hz, 2H). 86

C 736.5 ¹H NMR (400 MHz, CDCl₃): δ 9.28 (s, 2H), 8.50 (s, 1H), 8.08 (s,1H), 7.35-7.57 (m, 6H), 6.94- 6.96 (m, 3H), 6.77 (s, 1H), 6.38 (s, 1H),4.88- 4.90 (m, 1H), 4.14 (s, 2H), 3.60-3.86 (m, 17H), 3.31- 3.34 (m,2H), 2.66- 2.86 (m, 3H), 2.03-2.05 (m, 1H). 87

C 739.5 ¹H NMR (400 MHz, CDCl₃): δ 9.28 (s, 1H), 8.42 (s, 1H), 8.37-8.39(m, 2H), 8.06 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.62 (s,1H), 7.40- 7.45 (m, 3H), 6.09 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H),4.94-4.99 (m, 1H), 4.54 (t, J = 4.8 Hz, 4H), 3.86- 3.91 (m, 4H),3.66-3.75 (m, 12H), 2.73-2.92 (m, 3H), 2.20-2.22 (m, 1H). 88

A 820.5 ¹H NMR (400 MHz, CDCl₃): δ 9.35 (s, 1H), 8.63 (d, J = 7.6 Hz,1H), 8.45 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H), 7.87-7.90 (m,1H), 7.75 (d, J = 8.4 Hz, 1H), 7.53- 7.58 (m, 2H), 7.39 (s, 1H), 7.35(s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.87-4.92(m, 3H), 4.55 (t, J = 4.8 Hz, 2H), 4.24 (t, J = 4.8 Hz, 2H), 3.90 (t, J= 4.4 Hz, 3H), 3.66-3.73 (m, 12 H), 2.76-2.87 (m, 3H), 2.09- 2.16 (m,1H). 89

C 841.6 ¹H NMR: (400 MHz, DMSO-d₆) δ: 11.09 (s, 1H), 9.36 (s, 1H), 8.61(d, J = 2.4 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H),8.21 (s, 1H), 8.15 (dd, J = 2.8, 8.8 Hz, 1H), 7.95 (s, 1H), 7.65-7.57(m, 3H), 7.29 (s, 1H), 7.23- 7.18 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H),5.04 (dd, J = 5.6, 12.8 Hz, 1H), 4.31 (t, J = 6.4 Hz, 2H), 4.14 (br s,1H), 4.10-3.99 (m, 3H), 3.96 (s, 3H), 3.87 (d, J = 11.6 Hz, 2H), 3.74(dd, J = 5.6, 10.8 Hz, 2H), 3.02- 2.81 (m, 4H), 1.98-1.86 (m, 2H),1.85-1.72 (m, 4H), 1.63-1.15 (m, 9H). 90

A 744.5 ¹HNMR (400 MHz, CDCl₃): δ 9.35 (s, 1H), 8.60 (s, 1H), 8.50 (s,1H), 8.20 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H),7.49 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 10.0 Hz, 2H), 7.16 (d, J = 8.0Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.10 (s, 2H), 4.98-5.00 (m, 1H), 4.21(s, 2H), 4.07-4.10 (m, 2H), 3.90 (s, 3H), 3.44-3.54 (m, 7H), 2.76-2.87(m, 3H), 2.18-2.23 (m, 2H), 1.88- 1.92 (m, 3H), 1.72-1.75 (m, 4H). 91

C 798.6 1H NMR (400 MHz, CD₃OD): δ 9.33 (s, 1H), 8.51-8.53 (m, 2H),8.33- 8.34 (m, 1H), 8.09-8.11 (m, 1H), 7.84 (s, 1H), 7.59-7.62 (m, 3H),7.30 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H),5.32-5.35 (m, 1H), 3.99 (s, 3H), 3.40-3.47 (m, 13H), 2.69-2.71 (m, 6H),2.50-2.52 (m, 4H), 2.03- 2.18 (m, 5H), 1.59-1.60 (m, 6H). 92

A 786.5 ¹H NMR (400 MHz, CDCl₃): δ 9.32 (s, 1H), 8.68 (s, 1H), 8.58 (s,1H), 8.35 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.74 (d, J =8.4 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.27-7.34 (m, 2H),7.20 (d, J = 7.6 Hz, 1H), 4.92-4.96 (m, 1H), 4.61 (s, 2H), 4.23 (s, 2H),3.89-3.94 (m, 8H), 3.68-3.78 (m, 11H), 2.72 2.90 (m, 3H), 2.01- 2.12 (m,1H). 93

C 782.5 ¹H NMR (400 MHz, CDCl₃): δ 9.35 (br, 1H), 8.94 (s, 1H), 8.59 (s,1H), 8.21 (d, J = 8.0 Hz, 1H), 8.01-8.09 (m, 2H), 7.73 (d, J = 8.4 Hz,1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H),7.31 (d, J = 5.2 Hz, 1H), 7.24 (s, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H),4.85- 4.90 (m, 1H), 4.10 (t, J = 8.0 Hz, 1H), 3.98 (t, J = 6.4 Hz, 1H),3.87 (s, 3H), 3.51 (t, J = 6.4 Hz, 1H), 3.27-3.32 (m, 4H), 2.65- 2.85(m, 3H), 2.04-2.08 (m, 1H), 1.71-1.76 (m, 4H), 1.45-1.52 (m, 8H), 0.75-0.85 (m, 4H). 94

C 761.5 ¹HNMR (400 MHz, DMSO-d₆): δ: 11.04 (s, 1H), 9.29 (s, 1H), 8.58(d, J = 2.0 Hz, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H),8.12-8.16 (m, 2H), 7.92 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.56 (d, J =6.0 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.20-7.22 (m, 1H),6.92 (d, J = 4.4 Hz, 1H), 5.37 (s, 1H), 5.01-5.37 (m, 2H), 4.25 (t, J =6.0 Hz, 2H), 3.89 (s, 3H), 2.43-2.65 (m, 9H), 1.98 (t, J = 6.4 Hz, 3H).95

C 765.5 ¹HNMR (400 MHz, CDCl₃): δ: 9.32 (s, 1H), 8.59 (d, J = 4.8 Hz,1H), 8.49 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H), 8.08 (s, 1H),7.94 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.49(d, J = 8.4 Hz, 1H), 7.32 (s, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.07 (s,1H), 6.87 (d, J = 8.8 Hz, 1H), 5.52 (s, 1H), 4.94-4.97 (m, 2H), 4.08 (s,2H), 3.91 (s, 3H), 2.73-2.92 (m, 8H), 2.13-2.15 (m, 2H), 1.86- 1.88 (m,2H), 1.78-1.80 (m, 2H), 1.46-1.54 (m, 2H). 96

B 838.6 ¹H NMR: 400 MHz, DMSO-d6 δ: 11.09 (s, 1H), 9.38 (s, 1H), 8.64(d, J = 2.4 Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H),8.19 (dd, J = 2.4, 8.8 Hz, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.72- 7.59(m, 3H), 7.21 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 2.0, 8.8 Hz, 1H), 6.94(d, J = 8.4 Hz, 1H), 5.38- 5.26 (m, 1H), 5.06 (dd, J = 5.3, 12.9 Hz,1H), 4.24- 4.13 (m, 1H), 3.96 (s, 3H), 3.95-3.88 (m, 1H), 3.72 (d, J =15.2 Hz, 1H), 3.68- 3.63 (m, 1H), 3.53 (d, J = 7.2 Hz, 1H), 3.31 (s,2H), 3.07-2.75 (m, 4H), 2.74-2.54 (m, 4H), 2.44- 2.29 (m, 4H), 2.06-1.94(m, 1H), 1.50 (td, J = 7.0, 13.8 Hz, 4H), 1.33 (s, 4H). 97

B 775.5 1H NMR (400 MHz, CDCl₃): δ 8.42-8.48 (m, 2H), 8.17-8.23 (m, 2H),7.93 (d, J = 2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.51-7.58 (m, 1H),7.34 (s, 1H), 7.26-7.28 (m, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.05-7.17 (m,1H), 6.87 (d, J = 8.4 Hz, 1H), 5.52-5.54 (m, 1H), 4.96-4.98 (m, 2H),4.14-4.17 (m, 2H), 3.91 (s, 3H), 2.73-2.88 (m, 8H), 2.52-2.55 (m, 2H),2.02-2.15 (m, 3H), 1.81- 1.85 (m, 2H). 98

B 779.5 1H NMR (400 MHz, CDCl₃): δ 8.48 (s, 1H), 8.26 (d, J = 7.6 Hz,1H), 8.17 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.57-7.63 (m, 2H), 7.28-7.34 (m, 1H), 7.17-7.20 (m, 1H), 7.06 (s, 1H),6.90 (d, J = 8.4 Hz, 1H), 5.53-5.55 (m, 1H), 4.97-5.01 (m, 2H), 4.06-4.16 (m, 2H), 3.98 (s, 3H), 2.71-2.88 (m, 8H), 2.51- 2.53 (m, 1H),2.02-2.21 (m, 4H), 1.62-1.85 (m, 4H), 1.51-1.56 (m, 4H), 0.82-0.92 (m,2H). 99

A 773.5 1H NMR (400 Hz, DMSO-d6): δ 1.40-1.56 (m, 2H), 1.62-1.75 (m,2H), 1.83-2.09 (m, 2H), 2.34-2.50 (m, 3H), 2.58- 2.73 (m, 2H), 2.83-2.93(m, 1H), 3.01-3.13 (m, 2H), 3.37-3.52 (m, 8H), 3.77 (s, 2H), 3.95 (s,3H), 4.18 (s, 1H), 5.02-5.13 (m, 2H), 5.29-5.37 (m, 1H), 6.94 (d, J =8.0 Hz, 1H), 7.21-7.29 (m, 2H), 7.59- 7.65 (m, 2H), 7.80 (d, J = 7.2 Hz,1H), 7.97 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H),8.50 (d, J = 5.2 Hz, 1H), 8.63 (s, 1H), 9.35 (s, 1H), 11.11 (s, 1H). 100

C 771.6 ¹H NMR (400 MHz, CDCl₃): δ 1.65-1.67 (m, 6H), 1.74-1.81 (m, 2H),1.87-1.94 (m, 2H), 2.00- 2.06 (m, 1H), 2.09-2.14 (m, 1H), 2.18-2.24 (m,2H), 2.54-2.59 (m, 2H), 2.68-2.90 (m, 3H), 3.37- 3.53 (m, 5H), 3.91 (t,J = 7.6 Hz, 3H), 3.98 (d, J = 8.0 Hz, 3H), 4.39 (t, J = 6.4 Hz, 2H),4.90-4.94 (m, 1H), 6.45 (d, J = 1.6 Hz, 1H), 6.72 (d, J = 1.6 Hz, 1H),6.85 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 6 Hz, 1H), 7.50 (d, J = 8.0 Hz,1H), 7.56 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H),8.05 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.60(d, J = 5.6 Hz, 1H), 9.34 (s, 1H). 101

A 827.5 1H NMR (400 Hz, D6- DMSO): δ 1.56-1.59 (m, 2H), 1.71-1.77 (m,2H), 1.95-2.05 (m, 2H), 2.34- 2.46 (m, 3H), 2.50-2.67 (m, 3H), 2.83-2.93(m, 1H), 3.32-3.49 (m, 9H), 3.88-3.92 (m, 1H), 4.17- 4.20 (m, 1H), 4.55(t, J = 5.6 Hz, 1H), 5.05-5.13 (m, 2H), 5.46-5.49 (m, 1H), 7.25-7.28 (m,2H), 7.52 (d, J = 5.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.82 (d, J =8.0 Hz, 1H), 7.87 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H), 8.45(d, J = 6.0 Hz, 1H), 8.83 (s, 1H), 9.39 (s, 1H), 11.11 (s, 1H), 11.86(s, 1H). 102

C 775.5 ¹H NMR (400 MHz, DMSO-d₆): δ 1.73 (d, J = 7.2 Hz, 2H), 1.91 (d,J = 7.2 Hz, 2H), 2.01-2.08 (m, 1H), 2.51-2.67 (m, 8H), 2.83-2.94 (m,1H), 3.96 (s, 3H), 4.24 (t, J = 6.0 Hz, 2H), 5.12 (dd, J = 12.8, 5.2 Hz,1H), 5.31-5.52 (m, 2H), 6.99 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.6 Hz,1H), 7.36 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.75- 7.58 (m, 3H), 7.82(d, J = 8.2 Hz, 1H), 7.99 (s, 1H), 8.10-8.28 (m, 2H), 8.33 (d, J = 8.2Hz, 1H), 8.52 (s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 9.40 (s, 1H), 11.11 (s,1H). 103

ND 774.5 ¹H NMR (400 MHz, CD₃OD): δ 9.46 (s, 1H), 8.63 (d, J = 6.8 Hz,1H), 8.38 (s, 1H), 8.00 (d, J = 6.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H),7.67 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 4.8 Hz, 1H), 7.29 (s, 1H), 7.23(d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.05 (m, 1H), 4.54-4.45(m, 2H), 4.26-4.19 (m, 2H), 3.86 (m, 4H), 370- 3.65 (m, 12H), 2.86-2.62(m, 3H), 2.10-2.04 (m, 1H). 104

A 773.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.73-1.79 (m, 4H), 1.97-1.99 (m,2H), 2.31-2.37 (m, 2H), 2.40-2.49 (m, 2H), 2.54- 2.59 (m, 1H), 2.83-2.88(m, 1H), 3.38 (t, J = 6.4 Hz, 2H), 3.43-3.49 (m, 6H), 3.82-3.85 (m, 2H),3.75 (s, 3H), 4.16-4.18 (m, 1H), 4.20-4.26 (m, 2H), 4.43-4.47 (m, 1H),5.02- 5.07 (m, 1H), 5.31-5.34 (m, 1H), 6.62-6.64 (m, 1H), 6.78-6.79 (m,1H), 6.93 (t, J = 8.4 Hz, 1H), 7.59-6.72 (m, 3H), 7.96 (s, 1H),8.17-8.19 (m, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 6.4 Hz, 1H),8.62-8.63 (m, 1H), 9.35 (s, 1H), 11.06 (s, 1H). 105

A 841.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.56-1.60 (m, 2H), 1.74 (t, J = 6.4Hz, 2H), 1.99-2.04 (m, 2H), 2.33-2.39 (m, 3H), 2.55-2.66 (m, 3H), 2.83-2.91 (m, 1H), 3.11-3.13 (m, 2H), 3.36-3.44 (m, 6H), 3.55-3.64 (m, 2H),3.88-3.93 (m, 1H), 3.97 (s, 3H), 4.17-4.20 (m, 1H), 5.06-5.12 (m, 2H),5.47- 5.49 (m, 1H), 7.27 (s, 2H), 7.65 (d, J = 6.0 Hz, 1H), 7.70 (d, J =8.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.35 (s, 1H),8.50-8.53 (m, 2H), 8.90 (s, 1H), 9.40 (s, 1H), 11.10 (s, 1H). 106

B 759.6 ¹H NMR (400 MHz, DMSO-d6): δ 1.54-1.68 (m, 10H), 1.84-1.88 (m,2H), 2.12-2.14 (m, 1H), 2.77-2.93 (m, 5H), 3.40- 3.45 (m, 4H), 3.64-3.75(m, 4H), 3.91 (s, 3H), 4.09 (t, J = 6.4 Hz, 2H), 4.39- 4.46 (m, 1H),4.89-4.99 (m, 1H), 5.41-5.50 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 7.14-7.2(m, 1H), 7.32-7.35 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.76(d, J = 8.0 Hz, 1H), 7.92-8.00 (m, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.43(d, J = 2.0 Hz, 1H), 8.59 (d, J = 5.6 Hz, 1H), 9.33 (s, 1H). 107

C 771.6 1HNMR (400 MHz, CDCl₃): δ 1.61-1.65 (m, 2H), 1.72-1.77 (m, 4H),1.90-1.93 (m, 2H), 1.99- 2.04 (m, 1H), 2.14-2.22 (m, 3H), 2.44-2.49 (m,2H), 2.78-3.01 (m, 6H), 3.44-3.49 (m, 4H), 3.92 (s, 3H), 3.99-4.05 (m,2H), 4.14 (t, J = 6.2 Hz, 2H), 4.94-4.98 (m, 1H), 5.17- 5.20 (m, 1H),6.81 (d, J = 8.4 Hz, 1H), 7.19-7.21 (m, 1H), 7.33-7.37 (m, 2H), 7.49 (d,J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.90-7.93 (m,1H), 8.21 (d, J = 8.4 Hz, 1H), 8.35 (br, 1H), 8.45- 8.46 (m, 1H), 8.59(d, J = 5.6 Hz, 1H), 9.34 (s, 1H). 108

C 795.5 ¹H NMR (400 MHz, DMS0d-6): δ 1.43-1.44 (m, 4H), 1.70-1.74 (m,4H), 1.98-2.04 (m, 1H), 2.44-2.47 (m, 1H), 2.56- 2.60 (m, 1H), 2.65 (t,J = 6.0 Hz, 4H), 2.83-2.92 (m, 1H), 3.95 (s, 3H), 4.10 (t, J = 6.0 Hz,2H), 4.22 (t, J = 6.4 Hz, 2H), 5.07-5.11 (m, 1H), 5.30-5.35 (m, 1H),5.39-5.45 (m, 1H), 6.34- 6.37 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H),7.24-7.26 (m, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.59-7.65 (m, 3H), 7.72 (d,J = 8.0 Hz, 1H), 7.97 (s, 1H), 8.17-8.21 (m, 1H), 8.31 (d, J = 8.0 Hz,1H), 8.50 (d, J = 6.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 9.36 (s, 1H),11.10 (s, 1H). 109

C 795.5 ¹H NMR (400 MHz, DMS0d-6): δ 1.47 (s, 4H), 1.72-1.78 (m, 4H),2.02- 2.05 (m, 2H), 2.33 (s, 1H), 2.63-2.66 (m, 4H), 2.88- 2.89 (m, 1H),3.41-3.49 (m, 2H), 3.96 (s, 2H), 4.18-4.23 (m, 3H), 5.04- 5.12 (m, 2H),5.42 (br, 1H), 6.19 (s, 1H), 6.55-6.56 (m, 1H), 6.98 (d, J = 8.4 Hz,1H), 7.34 (d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 6.63 (s, 2H), 7.81-7.83 (m,1H), 7.95-7.97 (m, 2H), 8.21 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 7.2 Hz,1H), 8.50 (d, J = 4.0 Hz, 1H), 8.64 (s, 1H), 9.36 (s, 1H), 11.11 (s,1H). 110

C 779.5 ¹H NMR (400 MHz, DMSO-d₆): δ 1.36 (d, J = 7.6 Hz, 2H), 1.45 (d,J = 6.8 Hz, 2H), 1.52- 1.61 (m, 2H), 1.70-1.80 (m, 2H), 1.98-2.02 (m,3H), 2.54-2.70 (m, 6H), 2.89 (t, J = 16.6 Hz, 1H), 3.96 (s, 3H), 4.16(d, J = 5.0 Hz, 2H), 5.12 (dd, J = 12.8, 4.4 Hz, 1H), 5.36- 5.43 (m,2H), 6.77 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 7.34 (d, J =8.8 Hz, 1H), 7.42 (s, 1H), 7.60-7.64 (m, 3H), 7.83 (d, J = 8.0 Hz, 1H),7.97 (dd, J = 14.0, 6.4 Hz, 2H), 8.33 (d, J = 8.4 Hz, 1H), 8.21 (d, J =8.0 Hz, 1H), 8.50 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 9.37 (s, 1H), 11.11(s, 1H). 111

C 788.5 ¹HNMR (400 MHz, DMSO-d6): δ 1.98-2.02 (m, 1H), 2.54-2.73 (m,6H), 2.83-2.92 (m, 1H), 3.95-3.97 (m, 5H), 4.31- 4.34 (m, 2H), 4.50 (s,2H), 4.67-4.72 (m, 1H), 5.04- 5.13 (m, 2H), 5.42-5.48 (m, 1H), 6.67-6.69(m, 1H), 6.82 (s, 1H), 6.69- 7.01 (m, 1H), 7.33-7.36 (m, 1H), 7.53-7.55(m, 1H), 7.63-7.67 (m, 3H), 8.01 (s, 1H), 8.21-8.26 (m, 2H), 8.33-8.37(m, 1H), 8.51-8.55 (m, 1H), 8.65- 8.66 (m, 1H), 9.39 (s, 1H), 11.07 (s,1H). 112

A 788.5 ¹HNMR (400 MHz, CDCl₃): δ: 11.09 (s, 1H), 9.25 (s, 1H), 8.50 (s,1H), 8.59 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H),7.69-7.73 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J =8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.08-5.13 (m, 1H), 4.46 (d, J =4.4 Hz, 2H), 4.30-4.34 (m, 2H), 3.95 (s, 3H), 3.79 (s, 4H), 3.60 (s,4H), 3.56 (s, 4H), 3.53 (s, 4H), 2.85-2.88 (m, 1H), 2.61 (s, 2H). 113

C 786.5 [788.5] ¹HNMR (400 MHz, DMSO-d₆): δ 11.11 (s, 1H), 9.35 (s, 1H),8.50 (s, 1H), 8.38 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.75(d, J = 8.0 Hz, 1H), 7.62 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H),7.34 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 10.4 Hz, 1H), 5.13-5.08 (m, 1H),4.34-4.32 (m, 2H), 4.23- 4.21 (m, 2H), 3.91 (s, 3H), 3.77-3.71 (m, 4H),3.54- 3.46 (m, 12 H), 2.91-2.87 (m, 1H), 2.61-2.57 (m, 3H). 114

C 760.5 ¹H NMR (400 MHz, CDCl₃): δ 1.52-1.59 (m, 2H), 1.63-1.67 (m, 5H),1.83-1.90 (m, 1H), 2.11- 2.16 (m, 2H), 2.43-2.54 (m, 4H), 2.71-2.92 (m,4H), 3.39-3.49 (m, 6H), 3.95 (s, 3H), 4.08 (t, J = 6.4 Hz, 2H),4.23-4.29 (m, 1H), 4.94 (dd, J = 5.2, 12.0 Hz, 1H), 6.83 (d, J = 8.4 Hz,1H), 7.17 (dd, J = 2.0, 8.0 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.44 (d,J = 6.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.75 (d, J =8.4 Hz, 1H), 7.91 (dd, J = 2.4, 8.8 Hz, 1H), 8.14 (m, 1H), 8.21 (d, J =8.0 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 5.2 Hz, 1H), 9.34(s, 1H). 115

C 759.6 ¹H NMR (400 MHz, DMSO-d6): δ 1.34-1.38 (m, 2H), 1.40-1.58 (m,8H), 1.74-1.77 (m, 2H), 2.01-2.04 (m, 1H), 2.54- 2.61 (m, 1H), 2.84-2.93(m, 1H), 3.32-3.42 (m, 7H), 3.77-3.81 (m, 2H), 3.96 (s, 3H), 4.15 (t, J= 6.4 Hz, 2H), 4.21 (t, J = 8.8 Hz, 2H), 4.40-4.45 (m, 1H), 5.10 (dd, J= 12.8 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 8.0 Hz, 1H),7.39 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 6.0 Hz, 1H), 7.80(d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 8.01 (dd, J = 8.4 Hz, 1H), 8.29 (d, J= 8.0 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.58 (s, 1H), 9.36 (s, 1H),11.10 (s, 1H). 116

C 771.6 1HNMR (400 MHz, CDCl₃): δ 1.39-1.42 (m, 2H), 1.47-1.52 (m, 2H),1.64-1.70 (m, 2H), 1.77- 1.82 (m, 2H), 2.01-2.07 (m, 1H), 2.21-2.26 (m,2H), 2.54-2.64 (m, 3H), 2.75-2.90 (m, 5H), 3.42- 3.45 (m, 3H), 3.61-3.71(m, 4H), 3.95 (s, 3H), 4.35 (t, J = 6.2 Hz, 2H), 4.78- 4.82 (m, 1H),5.09-5.13 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 7.20-7.25 (m, 2H),7.60-7.63 (m, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 8.18-8.20 (m,1H), 8.31 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.65 (s, 1H),9.34 (s, 1H), 11.11 (s, 1H). 117

C 733.4 ¹H NMR (400 MHz, CD₃OD): δ 1.92-1.94 (m, 1H), 2.02-2.10 (m, 2H),2.62-2.65 (m, 5H), 3.90 (s, 3H), 4.97-5.02 (m, 2H), 5.10 (s, 2H), 5.37(t, J = 6 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 7.20-7.22 (m, 1H),7.34-7.41 (m, 2H), 7.45 (d, J = 2.0 Hz, 1H), 7.50-7.56 (m, 2H), 7.75-7.77 (m, 2H), 8.02-8.06 (m, 2H), 8.21 (d, J = 8.0 Hz, 1H), 8.37 (d, J =6.0 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H), 9.18 (s, 1H). 118

C 856.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.98-2.03 (m, 1H), 2.09-2.15 (m,1H), 2.20-2.24 (m, 1H), 2.70-2.87 (m, 5H), 4.01- 4.04 (m, 4H), 4.29-4.34(m, 1H), 4.46 (s, 2H), 4.75-4.79 (m, 1H), 4.89- 4.95 (m, 1H), 5.00-5.06(m, 1H), 5.33-5.40 (m, 2H), 5.65-5.70 (m, 1H), 6.53-6.55 (m, 1H), 6.79(s, 1H), 7.08-7.11 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.56-7.65 (m, 4H),7.95 (s, 1H), 8.19-8.30 (m, 3H), 8.60-8.64 (m, 2H), 9.38 (s, 1H). 119

C 990.7 ¹H NMR (400 MHz, DMSO-d₆): δ 0.93 (s, 9H), 1.35 (t, J = 6.8 Hz,3H), 1.77-1.78 (s, 1H), 2.02- 2.04 (m, 1H), 2.44 (s, 3H), 3.53-3.64 (m,14H), 3.80- 3.85 (m, 2H), 3.95 (s, 2H), 4.28 (s, 1H), 4.44 (d, J = 8.2Hz, 1H), 4.54 (d, J = 9.6 Hz, 1H), 4.58-4.63 (m, 2H), 4.90 (s, 1H), 5.12(s, 1H), 7.26-7.50 (m, 5H), 7.54 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 8.2Hz, 1H), 7.90 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.42-8.45 (m, 3H), 8.85(s, 1H), 8.97 (s, 1H), 9.41 (s, 1H), 11.92 (s, 1H). 120

C 790.5 ¹H NMR (400 MHz, DMSO-d6): δ 0.95 (s, 9H), 1.37-1.47 (m, 3H),1.75- 1.81 (m, 1H), 2.03-2.08 (m, 1H), 2.44 (s, 3H), 3.16-3.17 (m, 4H),3.29 (s, 2H), 3.54-3.63 (m, 2H), 3.89 (s, 2H), 4.06 (s, 3H), 4.26-4.31(m, 1H), 4.44- 4.51 (m, 3H), 4.56-4.61 (m, 1H), 4.90-4.96 (m, 1H),5.10-5.17 (m, 1H), 7.06-7.10 (m, 1H), 7.36- 7.38 (m, 2H), 7.42-7.48 (m,3H), 7.53-7.56 (m, 1H), 7.57-7.61 (m, 1H), 7.80 (s, 1H), 8.10-8.14 (m,1H), 8.32 (s, 1H), 8.44- 8.46 (m, 2H), 8.58 (d, J = 2.0 Hz, 1H), 8.97(s, 1H), 9.40 (s, 1H), 11.90-11.98 (m, 1H). 121

B 966.7 ¹H NMR (400 MHz, DMSOd-6): δ 0.93 (s, 9H), 1.36-1.47 (m, 3H),1.73- 1.80 (m, 1H), 1.96-2.09 (m, 2H), 3.23-3.60 (m, 16H), 3.79 (t, J =3.6 Hz, 2H), 3.96 (s, 2H), 4.28 (s, 1H), 4.42-4.46 (m, 3H), 4.54 (d, J =9.6 Hz, 1H), 4.90 (t, J = 7.6 Hz, 1H), 5.12 (s, 1H), 6.97 (d, J = 8.4Hz, 1H), 7.35-7.43 (m, 5H), 7.65-7.69 (m, 2H), 7.87 (s, 1H), 8.12-8.15(m, 1H), 8.37-8.43 (m, 2H), 8.51 (d, J = 5.6 Hz, 1H), 8.59 (d, J = 1.6Hz, 1H), 8.97 (s, 1H), 9.51 (s, 1H), 12.28 (s, 1H). 122

C 1010.7 ¹H NMR (400 MHz, DMSOd-6): δ 0.93 (s, 9H), 1.36 (d, J = 7.2 Hz,3H), 1.73-1.80 (m, 1H), 2.01- 2.05 (m, 1H), 2.44 (s, 1H), 3.51-3.60 (m,20H), 3.78 (t, J = 4.4 Hz, 2H), 3.95 (s, 2H), 4.06-4.10 (m, 1H), 4.27(s, 1H), 4.42-4.46 (m, 3H), 4.54 (d, J = 9.6 Hz, 1H), 4.90 (t, J = 7.2Hz, 1H), 5.12 (d, J = 3.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.35-7.38(m, 3H), 7.41-7.43 (m, 2H), 7.48 (d, J = 5.6 Hz, 1H), 7.56 (d, J = 8.0Hz, 1H), 7.77 (s, 1H), 8.10-8.13 (m, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.42(d, J = 6.0 Hz, 2H), 8.56 (d, J = 2.4 Hz, 1H), 8.97 (s, 1H), 9.35 (s,1H), 11.79 (s, 1H). 123

C 839.6 ¹HNMR (400 MHz, DMSO-d₆): δ: 11.11 (s, 1H), 9.39 (s, 1H), 8.91(s, 1H), 8.51 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 8.10 (s,1H), 7.83 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.64 (d, J =5.2 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 5.42-5.47 (m, 1H),5.09-5.14 (m, 1H), 4.36 (s, 1H), 4.18 (t, J = 6.4 Hz, 2H), 4.24 (t, J =4.8 Hz, 2H), 3.98 (s, 3H), 2.80- 2.91 (m, 1H), 2.74-2.76 (m, 2H),2.40-2.46 (m, 4H), 2.32 (t, J = 6.4 Hz, 2H), 2.05-2.07 (m, 4H), 1.76-1.82 (m, 4H), 1.44-1.48 (m, 4H). 124

C 774.5 1H NMR (400 MHz, CDCl₃): δ 8.49 (s, 1H), 8.22 (m, J = 7.6 Hz,1H), 8.17 (s, 1H), 7.94 (d, J = 2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H),7.59 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 1.2 Hz, 1H), 7.30-7.27 (m, 4H), 7.20-7.18 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.74 (d, J =8.4 Hz, 2H), 5.52-5.54 (m, 1H), 4.97-4.94 (m, 2H), 4.16 (t, J = 6.0 Hz,2H), 3.92 (s, 3H), 2.88-2.69 (m, 8H), 2.50 (t, J = 6.8 Hz, 2H),2.16-2.13 (m, 2H), 1.82-1.78 (m, 2H). 125

C 841.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.85-1.90 (m, 4H), 2.08-2.19 (m,2H), 2.20-2.26 (m, 2H), 2.44-2.57 (m, 4H), 2.70- 2.90 (m, 3H), 3.45-3.49(m, 2H), 3.53-3.56 (m, 6H), 3.88-3.91 (m, 2H), 4.22-4.29 (m, 3H), 4.47-4.48 (m, 1H), 4.90-4.94 (m, 1H), 5.53-5.55 (m, 1H), 6.51 (d, J = 8.0 Hz,1H), 6.77 (s, 1H), 7.47 (d, J = 17.2 Hz, 2H), 7.58 (s, 1H), 7.60 (d, J =8.4 Hz, 1H), 8.16 (s, 1H), 8.23-8.28 (m, 2H), 8.60 (s, 2H), 9.41 (s,1H). 126

B 796.6 ¹H NMR (400 MHz, DMSO-d6): δ 1.42-1.51 (m, 4H), 1.75-1.79 (m,2H), 2.03-2.06 (m, 1H), 2.54 (s, 3H), 2.58-2.68 (m, 5H), 2.81-2.94 (m,2H), 3.11-3.17 (m, 2H), 3.61- 3.71 (m, 3H), 3.98-4.11 (m, 6H), 4.15 (s,3H), 4.17-4.23 (m, 3H), 5.10- 5.14 (m, 1H), 5.25-5.31 (m, 1H), 7.03 (d,J = 8.4 Hz, 1H), 7.33-7.42 (m, 2H), 7.84-7.89 (m, 1H), 8.22-8.32 (m,3H), 8.55 (d, J = 8.0 Hz, 1H), 8.71 (s, 1H), 8.78 (d, J = 6.4 Hz, 1H),9.78 (s, 1H), 10.05 (brs, 1H), 10.51 (brs, 1H), 11.11 (s, 1H). 127

C 683.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.11-1.23 (m, 4H), 1.82-1.99 (m,4H), 2.30-2.39 (m, 3H), 2.60 (br, 4H), 2.86-2.94 (m, 3H), 3.17 (s, 2H),3.98 (s, 3H), 4.10 (br, 1H), 4.21 (d, J = 16.8 Hz, 1H), 4.32- 4.41 (m,3H), 5.05 (dd, J = 13.2 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 706-7.08 (m,2H), 7.53 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.69 (d, J =6.0 Hz, 1H), 7.95 (s, 1H), 8.02 (dd, J = 9.2 Hz, 1H), 8.30 (dd, J = 8.4Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.64 (s, 1H), 9.38 (s, 1H), 10.95 (s,1H). 128

C 697.6 ¹H NMR (400 MHz, DMSO-d6) δ 1.16-1.23 (m, 3H), 1.40-1.50 (m,2H), 1.61 (br, 1H), 1.76- 1.78 (m, 2H), 1.94-1.96 (m, 1H), 2.38-2.41 (s,3H), 2.51-2.56 (m, 4H), 2.82- 2.90 (m, 3H), 3.29-3.33 (m, 4H), 3.95 (s,3H), 4.18-4.22 (m, 1H), 4.30- 4.39 (m, 3H), 5.02-5.08 (m, 1H), 6.95 (d,J = 8.8 Hz, 1H), 7.05-7.06 (m, 2H), 7.50-7.69 (m, 3H), 7.91 (s, 1H),8.00 (dd, J = 8.8, 2.2 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.48 (d, J =5.8 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 9.33 (s, 1H), 10.95 (s, 1H). 129

C 818.5 ¹HNMR (400 MHz, CDCl₃): δ 9.25 (s, 1H), 8.48 (s, 1H), 8.39 (s,1H), 8.09 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.72 (d, J =8.4 Hz, 1H), 7.46 (s, 1H), 7.36-7.41 (m, 2H), 7.19-7.24 (m, 2H), 6.82(d, J = 8.8 Hz, 1H), 4.86-4.91 (m, 1H), 4.58- 4.63 (m, 1H), 4.45-4.48(m, 2H), 3.78-3.82 (m, 5H), 3.55-3.80 (m, 9H), 3.39-3.50 (m, 3H), 2.69-2.82 (m, 6H), 1.96-2.05 (m, 2H), 1.81-1.89 (m, 2H). 130

B 854.6 ¹H NMR (400 MHz, DMSO-d6): δ 1.74-1.80 (m, 4H), 1.85-1.92 (m,2H), 1.97-2.02 (m, 2H), 2.02-2.15 (m, 2H), 2.54- 2.58 (m, 2H), 2.67-2.91(m, 4H), 3.41-3.50 (m, 8H), 3.81-3.88 (m, 2H), 3.98 (s, 3H), 4.25 (t, J= 7.8 Hz, 2H), 4.44-4.49 (m, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H),5.33-5.40 (m, 1H), 6.66 (dd, J = 1.6, 8.4 Hz, 1H), 6.80 (d, J = 1.2 Hz,1H), 7.63-7.72 (m, 3H), 8.10 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.51 (d,J = 4.8 Hz, 2H), 8.92 (s, 1H), 9.39 (s, 1H), 11.06 (s, 1H). 131

A 796.5 1H NMR (400 MHz, DMSOd-6): δ 1.99-2.05 (m, 1H), 2.55-2.67 (m,3H), 2.84-2.93 (m, 1H), 3.51-3.60 (m, 16H), 3.77 (d, J = 3.6 Hz, 4H),4.02 (s, 3H), 4.28 (m, 2H), 4.45 (t, J = 3.6 Hz, 2H), 5.09- 5.13 (m,1H), 6.98 (d, J = 8.4 Hz, 1H), 7.32-7.35 (m, 1H), 7.41 (d, J = 0.8 Hz,1H), 7.70 (d, J = 8.0 Hz, 1H), 7.78-7.82 (m, 2H), 8.06 (s, 1H), 8.20-8.23 (m, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 6.4 Hz, 1H), 8.66(d, J = 1.6 Hz, 1H), 8.66 (s, 1H), 9.48 (s, 1H), 11.12 (s, 1H). 132

A 840.6 1HNMR (400 MHz, DMSO-d6): δ 2.01-2.05 (m, 1H), 2.56-2.67 (m,2H), 2.84-2.89 (m, 1H), 3.49-3.59 (m, 20H), 3.75- 3.79 (m, 4H), 3.96 (s,3H), 4.27-4.29 (m, 2H), 4.43- 4.45 (m, 2H), 5.09-5.13 (m, 1H), 6.96-6.99(m, 1H), 7.32-7.35 (m, 1H), 7.41-7.42 (m, 1H), 7.62- 7.65 (m, 2H),7.79-7.81 (m, 1H), 7.99 (s, 1H), 8.19-8.21 (m, 1H), 8.31- 8.34 (m, 1H),8.50-8.51 (m, 1H), 8.64-8.65 (m, 1H), 9.37 (s, 1H), 11.11 (s, 1H). 133

A 757.6 1H NMR (400 Hz, D6- DMSO): δ 1.24-1.35 (m, 7H), 1.46-1.57 (m,8H), 1.72-1.82 (m, 2H), 1.98- 2.01 (m, 3H), 2.57-2.74 (m, 3H), 2.81-2.99(m, 2H), 3.57-3.59 (m, 2H), 3.98 (s, 3H), 4.06-4.08 (m, 2H), 4.33 (s,2H), 5.03- 5.06 (m, 1H), 6.54-6.66 (m, 1H), 6.69 (s, 1H), 6.93-6.95 (m,1H), 7.57- 7.71 (m, 3H), 8.02 (s, 1H), 8.19-8.21 (m, 1H), 8.34- 8.36 (m,1H), 8.53-8.58 (m, 1H), 8.66 (s, 1H), 9.41 (s, 1H), 11.08 (s, 1H). 134

B 776.5 ¹HNMR (400 MHz, DMSO-d₆): δ 1.74-1.78 (m, 2H), 1.92-1.95 (m,2H), 2.03-2.07 (m, 1H), 2.54-2.62 (m, 4H), 2.68- 2.71 (m, 4H), 2.85-2.93(m, 1H), 3.96 (s, 3H), 4.23-4.27 (m, 2H), 5.09- 5.14 (m, 1H), 5.45-5.48(m, 1H), 5.55-5.58 (m, 1H), 7.01 (d, J = 8.8 Hz, 1H), 7.24-7.26 (m, 1H),7.36-7.38 (m, 1H), 7.45 (m, 1H), 7.62-7.68 (m, 3H), 7.82 (d, J = 8.0 Hz,1H), 7.99 (s, 1H), 8.21-8.24 (m, 1H), 8.33 (d, J = 8.0 Hz, 1H),8.49-8.51 (m, 1H), 8.64-8.65 (m, 1H), 9.37 (s, 1H), 11.12 (s, 1H). 135

B 783.6 ¹H NMR (400 MHz, DMSO-d₆): 1.60-1.80 (m, 6H), 1.92-2.07 (m, 5H),2.16-2.26 (m, 3H), 2.34- 2.40 (m, 2H), 2.55-2.67 (m, 4H), 2.84-2.93 (m,1H), 3.26-3.31 (m, 4H), 3.78-3.82 (m, 1H), 3.96 (s, 3H), 4.18 (t, J =6.0 Hz, 2H), 5.05-5.27 (m, 2H), 6.90-6.94 (m, 1H), 7.33- 7.35 (m, 1H),7.42 (s, 1H), 7.60-7.63 (m, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H),8.17-8.20 (m, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 6.0 Hz, 1H),8.62 (s, 1H), 9.36 (s, 1H), 11.12 (s, 1H). 136

C 797.5 1HNMR (400 MHz, DMSO-d₆): δ 1.61-1.65 (m, 2H), 1.77-1.80 (m,2H), 1.99-2.08 (m, 4H), 2.14-2.20 (m, 2H), 2.44- 2.46 (m, 3H), 2.55-2.61(m, 4H), 2.72-2.76 (m, 1H), 2.85-2.93 (m, 1H), 3.79-3.84 (m, 3H), 3.96(s, 3H), 4.04-4.09 (m, 2H), 4.17-4.20 (m, 2H), 5.10- 5.14 (m, 2H), 6.93(d, J = 8.4 Hz, 1H), 7.34-7.42 (m, 2H), 7.61-7.65 (m, 2H), 7.83 (d, J =8.0 Hz, 1H), 7.99 (s, 1H), 8.18-8.20 (m, 1H), 8.32 (d, J = 8.4 Hz, 1H),8.50 (d, J = 6.0 Hz, 1H), 8.62 (d, J = 0.8 Hz, 1H), 9.37 (s, 1H), 11.12(s, 1H). 137

C 810.6 ¹H NMR (400 MHz, DMSO-d6): δ 1.58-1.63 (m, 2H), 1.72-1.77 (m,2H), 2.03-2.11 (m, 3H), 2.33-2.47 (m, 8H), 2.54- 2.62 (m, 2H), 2.78-2.90(m, 3H), 3.41-3.48 (m, 3H), 3.75-3.79 (m, 1H), 3.80-3.87 (m, 1H), 4.02(s, 3H), 4.06 (s, 1H), 4.13- 4.18 (m, 3H), 5.10-5.14 (m, 1H), 5.25-5.28(m, 1H), 6.96-7.00 (m, 1H), 7.33-7.42 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H),7.80-7.84 (m, 2H), 8.06 (s, 1H), 8.23-8.26 (m, 1H), 8.39 (d, J = 8.0 Hz,1H), 8.57-8.67 (m, 2H), 9.49 (s, 1H), 11.12 (s, 1H). 138

B 788.5 ¹H NMR (400 MHz, DMSO-d6): δ 2.01-2.04 (m, 1H), 2.56-2.67 (m,2H), 2.83-2.93 (m, 1H), 3.52-3.59 (m, 12H), 3.78 (s, 4H), 4.29 (s, 2H),4.45 (s, 2H), 5.11 (d, J = 12.8 Hz, 1H), 6.98 (d, J = 8.8 Hz , 1H), 7.34(d, J = 8.4 Hz , 1H), 7.43 (s, 1H), 7.76-7.83 (m, 3H), 8.14- 8.18 (m,2H), 8.36-8.50 (m, 2H), 8.61-8.65 (m, 2H), 9.49 (s, 1H), 11.11 (s, 1H).139

B 770.5 ¹H NMR (400 MHz, DMSOd-6): δ 2.00-2.03 (m, 1H), 2.59-2.74 (m,2H), 2.87 (t, J = 11.6 Hz, 1H), 3.52-3.60 (m, 12H), 3.80 (d, J = 19.2Hz, 4H), 4.03 (s, 3H), 4.28 (s, 2H), 4.54 (s, 2H), 5.11 (d, J = 12.8 Hz,1H), 7.33 (d, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.78 (m, 2H), 7.86 (d, J =4.0 Hz, 1H), 8.13 (s, 1H), 8.27 (d, J = 11.2 Hz, 1H), 8.41 (d, J = 7.6Hz, 1H), 8.52 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 9.53 (s, 1H), 11.11 (s,1H). 140

A 766.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.99-2.05 (m, 1H), 2.26 (s, 3H),2.52-2.60 (m, 2H), 2.89 (s, 1H), 3.48-3.65 (m, 12H), 3.74-3.83 (m, 4H),4.04 (s, 3H), 4.24-4.31 (m, 2H), 4.44-4.50 (m, 2H), 5.08- 5.13 (m, 1H),7.32-7.34 (m, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H),7.79 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 6.0 Hz, 1H), 8.04-8.10 (m, 2H),8.40 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 6.4 Hz,1H), 9.52 (s, 1H), 11.11 (s, 1H). 141

C 776.5 1H NMR (400 Hz, DMSO-d6): δ 1.72-1.78 (m, 2H), 1.91-2.10 (m,4H), 2.54-2.57 (m, 2H), 2.67-2.72 (m, 3H), 3.30 (s, 3H), 3.97 (s, 3H),4.25 (t, J = 6.4 Hz, 2H), 5.11-5.18 (m, 2H), 5.41-5.48 (m, 1H), 7.01 (d,J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8, 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz,1H), 7.63-7.67 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 8.23(dd, J = 8.8, 2.4 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.44 (s, 2H), 8.52(d, J = 5.6 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 9.39 (s, 1H), 11.12 (s,1H). 142

C 856.5 ¹H NMR (400 MHz, CD₃OD): δ 1.90-1.94 (m, 2H), 1.99-2.04 (m, 1H),2.34-2.40 (m, 1H), 2.65- 2.70 (m, 4H), 3.46-3.50 (m, 1H), 3.55-3.61 (m,2H), 3.86-3.90 (m, 1H), 3.96 (s, 3H), 4.89 (m, 2H), 4.95-5.01 (m, 2H),5.24 (t, J = 4.6Hz, 1H), 5.53-5.59 (m, 1H), 7.12-7.24 (m, 3H), 7.42 (d,J = 5.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.70-7.72 (m, 2H), 7.88 (s,1H), 8.06 (d, J = 2.8 Hz, 1H), 8.28-8.30 (m, 2H), 8.42 (d, J = 6.4 Hz,1H), 8.67 (d, J = 2.0 Hz, 1H), 9.29 (s, 1H). 143

B 820.5 ¹H NMR (400 MHz, DMSO-d6): δ 2.01-2.06 (m, 1H), 2.54-2.68 (m,2H), 2.84-2.93 (m, 1H), 3.40-3.44 (m, 6H), 3.47- 3.51 (m, 4H), 3.56-3.58(m, 2H), 3.70 (br, 2H), 3.78-3.81 (m, 2H), 3.94 (s, 3H), 4.21 (br, 2H),4.52 (t, J = 4.0 Hz, 2H), 5.11 (d, J = 12.8 Hz, 1H), 7.26 (d, J = 8.4Hz, 1H), 7.34 (s, 1H), 7.64 (t, J = 6.8 Hz, 2H), 7.69 (d, J = 6.0 Hz,1H), 7.74 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H),8.34 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 9.40 (s, 1H), 11.12(s, 1H). 144

C 775.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.68-1.75 (m, 2H), 1.88-1.95 (m,2H), 2.03-2.08 (m, 1H), 2.16-2.23 (m, 2H), 2.52- 2.65 (m, 3H), 2.85-2.93(m, 1H), 3.08-3.14 (m, 2H), 3.31 (m, 1H), 3.96 (s, 3H), 4.24 (t, J = 6.4Hz, 2H), 4.94-5.05 (m, 2H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 6.81 (d, J= 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 2.0, 8.4 Hz, 1H),7.44 (d, J = 2.0 Hz, 1H), 7.61-7.70 (m, 3H), 7.82 (d, J = 8.0 Hz, 1H),7.99 (s, 1H), 8.19- 8.21 (m, 2H), 8.32 (d, J = 8.0 Hz, 1H), 8.51 (m,1H), 8.65 (d, J = 2.0 Hz, 1H), 9.38 (m, 1H), 11.12 (s, 1H). 145

C 779.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.32-1.38 (m, 2H), 1.42-1.47 (m,2H), 1.53-1.61 (m, 2H), 1.71-1.78 (m, 2H), 2.01- 2.07 (m, 1H), 2.15-2.22(m, 2H), 2.53-2.61 (m, 4H), 2.84-2.94 (m, 1H), 3.08-3.15 (m, 2H), 4.14-4.17 (m, 5H), 4.91-5.06 (m, 2H), 5.12 (dd, J = 5.6, 12.8 Hz, 1H), 6.78(d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 2.0, 8.4Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 2.0, 8.4 Hz, 1H), 7.81-7.88 (m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 8.20-8.28 (m, 3H), 8.56 (d, J =8.4 Hz, 1H), 8.71-8.76 (m, 2H), 9.80 (s, 1H), 11.12 (s, 1H). 146

C 763.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.67-1.75 (m, 2H), 1.87-197 (m,2H), 2.03-2.07 (m, 1H), 2.20- 2.23 (m, 2H), 2.53-2.67 (m, 4H), 2.85-2.94(m, 1H), 3.98 (s, 3H), 4.23 (t, J = 6.0 Hz, 2H), 4.42-4.49 (m, 4H),5.10-5.14 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H),7.34-7.36 (m, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.63-7.69 (m, 3H), 7.82 (d,J = 8.4 Hz, 1H), 8.00 (s, 1H), 8.19-8.21 (m, 2H), 8.34 (d, J = 8.0 Hz,1H), 8.51 (d, J = 6.0 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 9.40 (s, 1H),11.12 (s, 1H). 147

C 778.5 ¹HNMR (400 MHz, CDCl₃): δ: 9.32 (s, 1H), 8.58 (d, J = 5.6 Hz,1H), 8.49 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J =7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.32 (s, 2H), 7.17 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.4 Hz,2H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 7.6 Hz, 2H), 5.49 (s, 1H),4.94 (s, 2H), 4.07 (t, J = 6.4 Hz, 2H), 3.91 (s, 3H), 2.68-2.88 (m, 8H),2.57 (t, J = 6.8 Hz, 2H), 2.01 (s, 2H), 1.83 (t, J = 6.8 Hz, 3H), 1.62-1.65 (m, 2H). 148

B 827.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.73-1.79 (m, 4H), 1.95-2.01 (m,2H), 1.99-2.04 (m, 2H), 2.33-2.39 (m, 2H), 2.44- 2.46 (m, 2H), 2.54-2.67(m, 1H), 2.82-2.91 (m, 1H), 3.37-3.49 (m, 8H), 3.81-3.84 (m, 2H), 4.17-4.25 (m, 3H), 4.43-4.48 (m, 1H), 5.01-5.06 (m, 1H), 5.45-5.50 (m, 1H),6.61- 6.64 (m, 1H), 6.77 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H),7.73 (d, J = 6.8 Hz, 1H), 7.97 (s, 1H), 8.471-8.43 (m, 2H), 8.54 (d, J =6.4 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H), 11.06 (s, 1H),12.44 (s, 1H). 149

B 780.5 ¹HNMR (400 MHz, DMSO-d₆): δ 1.36-1.49 (m, 4H), 1.66-1.77 (m,4H), 2.02-2.06 (m, 1H), 2.54- 2.68 (m, 6H), 2.81-2.94 (m, 3H), 3.16-3.17(m, 1H), 3.99 (s, 3H), 4.15- 4.18 (m, 2H), 5.09-5.14 (m, 1H), 5.44-5.53(m, 1H), 7.02 (d, J = 8.8 Hz, 1H), 7.16-7.18 (m, 1H), 7.33- 7.35 (m,1H), 7.45 (m, 1H), 7.54-7.56 (m, 1H), 7.65-7.67 (m, 1H), 7.72- 7.73 (m,1H), 7.81-7.83 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 8.22-8.24 (m, 1H),8.35-8.37 (d, J = 8.0 Hz, 1H), 8.52-8.57 (m, 1H), 8.64-8.65 (m, 1H),9.42 (s, 1H), 11.11 (s, 1H). 150

B 804.5 ¹H NMR: (400 MHz, DMSO-d₆) δ: 10.95 (s, 1H), 9.14 (br s, 1H),8.15 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.18 -7.04 (m, 5H), 6.83 (d, J =6.7 Hz, 2H), 6.65 (d, J = 8.5 Hz, 1H), 6.61 (s, 1H), 6.54- 6.47 (m, 3H),6.26 (d, J = 8.5 Hz, 2H), 5.05 (dd, J = 5.0, 13.3 Hz, 1H), 4.38- 4.26(m, 1H), 4.24-4.11 (m, 1H), 3.78 (br t, J = 6.5 Hz, 4H), 3.54-3.31 (m,3H), 3.03-2.83 (m, 8H), 2.62-2.52 (m, 3H), 2.47- 2.31 (m, 1H), 2.21-2.04(m, 3H), 2.01-1.87 (m, 3H), 1.71 (br d, J = 10.7 Hz, 2H). 151

B 780.5 1H NMR (400 Hz, DMSO-d6): δ 1.21-1.26 (m, 1H), 1.33-1.48 (m,4H), 1.69-1.73 (m, 4H), 1.01-2.07 (m, 1H), 2.57- 2.68 (m, 5H), 2.79-2.93(m, 3H), 4.02 (s, 3H), 4.16 (t, J = 6.4 Hz, 2H), 5.09- 5.13 (m, 2H),5.41-5.48 (m, 1H), 7.01 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.4, 1.6 Hz,1H), 7.46 (d, J = 0.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.79-7.83 (m,2H), 8.07 (s, 1H), 8.23 (dd, J = 8.4, 1.2 Hz, 1H), 8.37- 8.45 (m, 3H),8.58 (d, J = 6.0 Hz, 1H), 8.67 (s, 1H), 9.49 (s, 1H), 11.11 (s, 1H),.152

A 788.5 ¹H NMR (400 MHz, DMSO-d6): δ 2.01-2.06 (m, 1H), 2.53-2.73 (m,6H), 2.84-2.92 (m, 1H), 3.59 (s, 2H), 3.81 (t, J = 6.8 Hz, 2H), 3.96 (s,3H), 5.07-5.14 (m, 3H), 5.42- 5.47 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H),7.28-7.33 (m, 3H), 7.48 (d, J = 8.4 Hz, 1H), 7.62-7.65 (m, 2H), 7.84 (d,J = 8.0 Hz, 1H), 7.99 (s, 1H), 8.20-8.24 (m, 2H), 8.33 (d, J = 8.0 Hz,1H), 8.51 (m, 1H), 8.65 (d, J = 2.4 Hz, 1H), 9.38 (m, 1H), 11.11 (s,1H). 153

B 839.6 1H NMR (400 MHz, DMSO-d6): δ 1.38-1.41 (m, 2H), 1.54-1.59 (m,4H), 1.92-1.96 (m, 3H), 2.23-2.45 (m, 5H), 2.82- 3.02 (m, 2H), 3.34 (t,J = 6.0 Hz, 2H), 3.56-3.62 (m, 1H), 3.67-3.79 (m, 3H), 4.04-4.05 (m,1H), 4.14- 4.21 (m, 6H), 5.01-5.06 (m, 1H), 5.29-5.35 (m, 1H), 6.61 (d,J = 8.0 Hz, 1H), 6.74 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.61 (d, J =8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.21-8.25 (m, 3H), 8.53 (d, J =8.4 Hz, 1H), 8.68 (d, J = 1.6 Hz, 1H), 8.77 (d, J = 6.8 Hz, 1H), 9.77(s, 1H), 11.07 (s, 1H). 154

C 839.6 1HNMR (400 MHz, DMSO-d6): δ 1.26 (s, 4H), 1.36-1.37 (m, 2H),1.49- 1.54 (m, 2H), 1.97-2.00 (m, 1H), 2.29-2.42 (m, 4H), 2.53-2.59 (m,2H), 2.83-2.91 (m, 1H), 3.17- 3.23 (m, 3H), 3.65-3.71 (m, 1H), 3.78-3.89(m, 2H), 3.96 (s, 3H), 3.98- 4.02 (m, 1H), 4.11-4.22 (m, 3H), 4.33-4.36(m, 1H), 5.04-5.08 (m, 1H), 5.28-5.34 (m, 1H), 6.68- 6.70 (m, 1H),6.83-6.84 (m, 1H), 6.93-6.95 (m, 1H), 7.61-7.66 (m, 3H), 7.98 (s, 1H),8.17-8.20 (m, 1H), 8.31-8.33 (m, 1H), 8.49-8.51 (m, 1H), 8.63- 8.64 (m,1H), 9.36 (s, 1H), 11.07 (s, 1H). 155

C 794.5 1H NMR (400 MHz, DMSO-d6): δ 2.33-2.50 (m, 6H), 2.54-2.60 (m,1H), 2.83-2.93 (m, 1H), 3.68 (t, J = 4.4 Hz, 2H), 3.96 (s, 3H), 4.01 (d,J = 3.6 Hz, 2H), 4.15 (t, J = 4.0 Hz, 2H), 4.28-4.33 (m, 1H), 4.45-4.49(m, 2H), 4.04 (s, 1H), 5.06 (d, J = 5.2 Hz, 1H), 5.31-5.36 (m, 1H),5.43-5.48 (m, 1H), 6.71 (dd, J = 2.0 Hz, 1H), 6.88 (t, J = 9.2 Hz, 2H),6.95 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7.61-7.65 (m, 1H),7.91 (d, J = 2.8 Hz, 1H), 7.99 (s, 1H), 8.18- 8.20 (m, 1H), 8.33 (d, J =8.0 Hz, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 9.37(s, 1H), 11.08 (s, 1H). 156

C 792.5 1H NMR (400 MHz, DMSO-d6): δ 1.93-2.01 (m, 3H), 2.54-2.70 (m,6H), 2.85 (t, J = 7.2 Hz, 2H), 3.45 (t, J = 6 Hz, 2H), 3.79-3.81 (m,2H), 4.15 (s, 3H), 4.22-4.26 (m, 2H), 4.43-4.45 (m, 1H), 5.03- 5.10 (m,3H), 5.43-5.46 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 7.04 (d,J = 8.4 Hz, 1H), 7.46- 7.56 (m, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.88 (d,J = 8.4 Hz, 1H), 8.21-8.30 (m, 4H), 8.55 (d, J = 8 Hz, 1H), 8.71-8.79(m, 2H), 9.77 (s, 1H), 11.07 (s, 1H). 157

C 797.5 1HNMR (400 MHz, DMSO-d6): δ 1.61-1.66 (m, 2H), 1.75-1.82 (m,2H), 1.99-2.06 (m, 4H), 2.29-2.33 (m, 2H), 2.43- 2.45 (m, 3H), 2.55-2.61(m, 3H), 2.56-2.93 (m, 1H), 3.06-3.09 (m, 1H), 3.31 (s, 1H), 3.80-3.88(m, 3H), 3.96 (s, 3H), 4.00-4.06 (m, 2H), 4.18 (t, J = 7.4 Hz, 2H),5.10-5.14 (m, 1H), 5.28-5.33 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H),7.33-7.36 (m, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.61-7.64 (m, 2H), 7.83 (d,J = 8.4 Hz, 1H), 7.98 (s, 1H), 8.18- 8.20 (m, 1H), 8.32 (d, J = 8.0 Hz,1H), 8.50 (d, J = 5.6 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 9.37 (s, 1H),11.12 (s, 1H) 158

C 823.5 1H NMR (400 MHz, DMSO-d6): δ 1.45-1.47 (m, 2H), 1.89-1.92 (m,2H), 1.97-2.07 (m, 3H), 2.40-2.44 (m, 4H), 2.55- 2.67 (m, 1H), 2.84-2.94(m, 1H), 3.16-3.25 (m, 2 H), 3.56-3.64 (m, 1H), 4.05 (s, 3H), 4.10-4.13(m, 2H), 4.42-4.45 (m, 1H), 4.51-4.58 (m, 3H), 5.10- 5.15 (m, 1H),5.31-5.35 (m, 1H), 6.78 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.40- 7.42(m, 1H), 7.51 (s, 1H), 7.85-7.89 (m, 2H), 8.10 (s, 1H), 8.21-8.24 (m,1H), 8.35 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.62 (d, J =6.0 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 9.54 (s, 1H), 11.12 (s, 1H). 159

C 788.5 1H NMR (400 MHz, DMSO-d6): δ 1.99-2.03 (m, 2H), 2.21-2.24 (m,2H), 2.54-2.67 (m, 2H), 2.83-2.92 (m, 1H), 3.16- 3.27 (m, 2H), 3.95-3.98(m, 4H), 3.30-3.34 (m, 2H), 4.49 (s, 2H), 4.66- 4.72 (m, 2H), 5.01-5.08(m, 2H), 6.68 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H), 6.98 (d, J = 8.4 Hz,1H), 7.37 (dd, J = 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.62- 7.67 (m,3H), 7.99 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H),8.33 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.65 (d, J = 2.0 Hz,1H), 9.37 (s, 1H), 11.07 (s, 1H). 160

B 792.5 1H NMR (400 MHz, DMSO-d6): δ 1.88-1.95 (m, 2H), 1.97-2.03 (m,2H), 2.16-2.23 (m, 2H), 2.54-2.60 (m, 1H), 2.67- 2.76 (m, 2H), 2.83-2.92(m, 1H), 3.14-3.21 (m, 2H), 3.43 (t, J = 6.4 Hz, 2H), 3.84 (d, J = 8.8Hz, 2H), 3.97 (s, 3H), 4.23- 4.27 (m, 2H), 4.43-4.48 (m, 1H), 4.56-4.63(m, 1H), 5.00-5.08 (m, 2H), 6.66 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 6.98(d, J = 8.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.24-7.27 (m, 1H),7.62-7.66 (m, 3H), 8.00 (s, 1H), 8.16 (d, J = 2.8 Hz, 1H), 8.21 (d, J =8.4 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.65(d, J = 2.4 Hz, 1H), 9.38 (s, 1H), 11.07 (s, 1H). 161

C 789.5 1H NMR (400 MHz, DMSO-d6): δ 2.30-2.36 (m, 2H), 2.40-2.46 (m,3H), 2.54-2.58 (m, 2H), 2.82-2.91 (m, 1H), 3.44- 3.47 (m, 2H), 3.54-3.57(m, 10H), 3.85 (d, J = 9.2 Hz, 2H), 3.95 (s, 3H), 4.20-4.25 (m, 3H),4.48- 4.50 (m, 1H), 5.04 (t, J = 12.8 Hz, 1H), 5.28-5.33 (m, 1H), 6.62(d, J = 8.4 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H),7.60-7.62 (m, 3H), 7.97 (s, 1H), 8.17- 8.20 (m, 1H), 8.49 (d, J = 6.0Hz, 1H), 8.63 (d, J = 2.4 Hz, 1H), 9.36 (s, 1H), 11.07 (s, 1H). 162

A 801.6 1H NMR (400 MHz, DMSO-d6): δ 1.56 (s, 8H), 1.98-2.01 (m, 1H),2.34- 2.46 (m, 6H), 2.59-2.67 (m, 2H), 2.83-2.92 (m, 1H), 3.38-3.42 (m,6H), 3.83 (d, J = 5.6 Hz, 2H), 3.96 (s, 3H), 4.18-4.25 (m, 3H), 4.44 (s,1H), 5.03- 5.07 (m, 1H), 5.29-5.33 (m, 1H), 6.63 (d, J = 7.6 Hz, 1H),6.78 (s, 1H), 6.93 (d, J = 8.8 Hz, 1H), 7.61- 7.63 (m, 3H), 7.98 (s,1H), 8.18 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.49 (d, J =5.6 Hz, 1H), 8.64 (s, 1H), 9.36 (s, 1H), 11.07 (s, 1H). 163

C 745.5 1H NMR (400 MHz, DMSO-d6): δ 1.94-2.00 (m, 1H), 2.31-2.48 (m,4H), 3.97 (s, 3H), 2.57 (s, 2H), 2.81-2.89 (m, 1H), 3.47-3.49 (m, 2H),3.54- 3.64 (m, 6H), 3.84-3.89 (m, 2H), 4.21-4.29 (m, 3H), 4.52 (s, 1H),5.02- 5.06 (m, 1H), 5.29-5.35 (s, 1H), 6.63-6.66 (m, 1H), 6.79 (d, J =2.0 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 7.59-7.66 (m, 2H), 7.69 (d, J =6.0 Hz, 1H), 7.99 (s, 1H), 8.17-8.20 (m, 1H), 8.34 (d, J = 8.0 Hz, 1H),8.53 (d, J = 6.0 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H), 9.40 (s, 1H), 11.07(s, 1H). 164

C 785.5 ¹H NMR (400 MHz, CDCl₃): δ 1.52-1.57 (m, 3H), 1.61-1.65 (m, 2H),1.70-1.74 (m, 2H), 1.98- 2.01 (m, 2H), 2.13-2.17 (m, 1H), 2.34-2.41 (m,2H), 2.47-2.50 (m, 2H), 2.78-2.88 (m, 2H), 3.20- 3.28 (m, 2H), 3.54-3.72(m, 3H), 4.00-4.10 (m, 3H), 4.39-4.44 (m, 1H), 4.95 (dd, J = 5.2, 12.0Hz, 1H), 5.31-5.42 (m, 4H), 6.82 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.8Hz, 1H), 7.31-7.34 (m, 2H), 7.48- 7.51 (m, 2H), 7.68 (s, 1H), 7.77 (d, J= 8.8 Hz, 1H), 7.87 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.32(s, 1H), 8.41-8.45 (m, 2H), 9.23 (s, 1H). 165

C 785.5 1HNMR (400 MHz, DMSO-d6): δ 1.35-1.38 (m, 2H), 1.47-1.57 (m,4H), 1.74-1.81 (m, 4H), 1.99-2.07 (m, 2H), 2.32- 2.39 (m, 2H), 2.57 (s,1H), 2.62-2.67 (m, 2H), 2.82- 2.91 (m, 1H), 3.12-3.18 (m, 3H), 3.41-3.51(m, 4H), 3.85-3.89 (m, 1H), 4.17-4.20 (m, 2H), 5.09- 5.14 (m, 1H),5.18-5.22 (m, 1H), 6.92 (d, J = 8.4 Hz, 1H), 7.33-7.36 (m, 1H), 7.42 (d,J = 1.6 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H),7.76 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 8.10-8.12 (m, 1H), 8.29 (d, J =8.0 Hz, 1H), 8.42 (d, J = 6.0 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 9.35(s, 1H), 11.11 (s, 1H), 11.81 (s, 1H). 166

C 785.5 1H NMR (400 MHz, DMSO-d6): δ 1.31-1.37 (m, 2H), 1.48-1.50 (m,2H), 1.55-1.57 (m, 2H), 1.76-1.79 (m, 4H), 2.03- 2.06 (m, 1H), 2.18-2.27(m, 2H), 2.55-2.70 (m, 3H), 2.85-2.92 (m, 1H), 3.06-3.17 (m, 4H), 3.42-3.48 (m, 3H), 3.57-3.60 (m, 1H), 3.79-3.83 (m, 1H), 4.17 (t, J = 5.2 Hz,2H), 5.11-5.15 (m, 2H), 6.91 (d, J = 8.8 Hz, 1H), 7.33-7.36 (m, 1H),7.42 (s, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.77(s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 8.09-8.12 (m, 1H), 8.29 (d, J = 8.0Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 9.35 (s,1H), 11.10 (s, 1H), 11.86 (s, 1H). 167

C 776.5 1HNMR (400 MHz, DMSO-d6): δ 1.99-2.03 m, 2H 2.23-2.27 (m, 2H),2.56-2.60 (m, 2H), 2.81- 2.94 (m, 1H), 3.92-3.94 (m, 1H), 3.96 (s, 3H),4.24-4.32 (m, 4H), 4.48- 4.52 (m, 4H), 4.65-4.72 (m, 1H), 5.03-5.08 (m,1H), 6.65-6.67 (m, 1H), 6.80-6.81 (m, 1H), 6.97 (t, J = 8.0 Hz, 1H),7.45-7.46 (m, 1H), 7.53-7.55 (m, 1H), 7.61-7.66 (m, 3H), 7.97 (s, 3H),8.16-8.21 (m, 1H), 8.31-8.34 (m, 2H), 8.49-8.50 (m, 1H), 8.63- 8.64 (m,1H), 9.36 (s, 1H), 11.07 (s, 1H). 168

B 780.5 1HNMR (400 MHz, DMSO-d6): δ 1.86-1.93 (m, 2H), 1.91-2.04 (m,2H), 2.19-2.27 (m, 2H), 2.69-2.77 (m, 2H), 2.81- 2.94 (m, 2H), 3.39-3.46(m, 2H), 3.81-3.84 (m, 2H), 3.96 (s, 3H), 4.14- 4.28 (m, 4H), 4.41-4.54(m, 3H), 5.02-5.10 (m, 1H), 6.65-6.67 (m, 1H), 6.80-6.81 (m, 1H), 6.97(t, J = 8.0 Hz, 1H), 7.18-7.20 (m, 1H), 7.32-7.34 (m, 1H), 7.59-7.66 (m,3H), 7.98 (s, 1H), 8.16-8.21 (m, 2H), 8.31-8.34 (m, 1H), 8.49-8.50 (m,1H), 8.63- 8.64 (m, 1H), 9.36 (s, 1H), 11.07 (s, 1H). 169

A 815.6 1H NMR (400 MHz, DMSO-d6): δ 1.79-1.84 (m, 2H), 1.94-2.01 (m,1H), 2.37-2.40 (m 2H), 2.43-2.49 (m, 4H), 2.52- 2.62 (m, 2H), 2.82-2.91(m, 1H), 3.48-3.56 (m, 6H), 3.60 (s, 2H), 3.81- 3.84 (m, 2H), 3.96 (s,2H), 4.17-4.30 (m, 3H), 4.35 (s, 3H), 4.43-4.49 (m, 1H), 5.00-5.09 (m,1H), 5.31- 5.39 (m, 1H), 6.56-6.66 (m, 1H), 6.76 (s, 1H), 6.94 (d, J =8.4 Hz, 1H), 7.52- 7.67 (m, 2H), 7.67-7.85 (m, 1H), 7.99 (s, 1H),8.13-8.52 (m, 3H), 8.64 (d, J = 1.6 Hz, 1H), 9.28-9.62 (m, 1H), 11.07(s, 1H). 170

A 773.5 1H NMR (400 MHz, DMSO-d6): δ 1.71-1.77 (m, 4H), 1.94-1.97 (m,3H), 2.54-2.58 (m, 1H), 2.86-2.88 (m, 3H), 3.16 (d, J = 3.6 Hz, 1H),3.38-3.46 (m, 8H), 3.75 (d, J = 6.8 Hz, 1H), 3.80-3.84 (m, 2H), 4.03 (s,3H), 4.19- 4.23 (m, 2H), 4.41-4.42 (m, 1H), 4.83-4.90 (m, 1H), 5.01-5.06(m, 1H), 6.61- 6.63 (m, 1H), 6.76 (d, J = 0.8 Hz, 1H), 6.95 (d, J = 8.4Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.88 (d, J= 6.0 Hz, 1H), 8.08 (s, 1H), 8.20-8.22 (m, 1H), 8.41 (d, J = 8.0 Hz,1H), 8.61 (d, J = 6.4 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 9.55 (s, 1H),11.06 (s, 1H). 171

C 807.5 ¹H NMR: (400 MHz, DMSO-d₆) δ = 11.11 (s, 1H), δ = 9.35 (s, 1H) δ= 8.64 (s, 1H), 8.49-8.48 (d, J = 4 Hz 1H), 8.33-8.31 (d, J = 8 Hz 1H),δ = 8.17 (s, 1H), δ = 7.97 (s, 1H) 7.85- 7.83 (d, J = 8 Hz 1H), 7.62-7.61 (d, J = 4 Hz 2H), 7.43 (s, 1H), 6.94-6.92 (d, J = 8 Hz 1H), 5.31-5.29 (m, 1H), 5.12-5.10 (m, 1H), 4.34 (s, 5H), 4.25-4.23 (d, J = 8 Hz1H), 3.95 (s, 3H), 2.77 (m, 2H), 2.73 (m, 4H), 2.53-2.52 (m, 1H),2.39-2.38 (m, 4H), 1.91-1.90 (m, 4H), 1.75 (m, 2H), 1.43 ( m, 2H), 1.41(m, 2H). 172

C 761.5 ¹H NMR (400 MHz, DMSO-d6): δ 1.68-1.77 (m, 2H), 1.89-1.96 (m,2H), 2.02-2.08 (m, 1H), 2.53-2.69 (m, 8H), 2.85- 2.94 (m, 1H), 4.25 (t,J = 6.2 Hz, 2H), 5.05-5.14 (m, 2H), 5.41-5.47 (m, 1H), 7.01 (d, J = 8.4Hz, 1H), 7.26-7.45 (m, 4H), 7.80- 7.84 (m, 2H), 7.99-8.03 (m, 2H),8.18-8.21 (m, 2H), 8.51-8.68 (m, 3H), 9.77 (s, 1H), 11.11 (s, 1H), 13.17(s, 1H). 173

A 763.5 ¹H NMR (400 MHz, DMSO-d6): δ 2.02-2.08 (m, 1H), 2.52-2.76 (m,6H), 2.85-2.93 (m, 1H), 3.89-3.95 (m, 2H), 4.37- 4.42 (m, 2H), 4.49 (s,2H), 5.06-5.14 (m, 2H), 5.40- 5.47 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H),7.30-7.33 (m, 1H), 7.38-7.40 (m, 1H), 7.46-7.48 (m, 2H), 7.62- 7.64 (m,2H), 7.82-7.84 (m, 2H), 8.14-8.17 (m, 1H), 8.24 (d, J = 2.8 Hz, 1H),8.36-8.38 (m, 1H), 8.49 (d, J = 6 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H),9.47 (s, 1H), 11.11 (s, 1H), 12.14-12.28 (m, 1H). 174

ND 784.5 1H NMR (400 MHz, DMSO-d6): δ 1.60 (s, 6H), 1.62-1.69 (m, 2H),1.77- 1.82 (m, 2H), 2.01-2.06 (m, 1H), 2.30-2.44 (m, 4H), 2.54-2.67 (m,2H), 2.84-2.93 (m, 1H), 3.31 (br, 2H), 3.38 (s, 2H), 3.45 (t, J = 6.4Hz, 2H), 3.96 (s, 3H), 4.20 (t, J = 6.4 Hz, 3H), 5.11 (dd, J = 12.8 Hz,1H), 5.28-5.34 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.4 Hz,1H), 7.42 (s, 1H), 7.61-7.64 (m, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.99 (s,1H), 8.19 (dd, J = 8.4 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.50 (d, J =5.6 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 9.37 (s, 1H), 11.11 (s, 1H). 175

C 797.5 1H NMR (400 Hz, D6- DMSO): δ 1.44-1.58 (m, 5H), 1.75-1.79 (m,2H), 1.92 (s, 6H), 2.01-2.05 (m, 2H), 2.50-2.61 (m, 2H), 2.83-2.94 (m,1H), 3.40 (t, J = 6.4 Hz, 2H), 3.86-3.89 (m, 1H), 3.96 (s, 3H), 4.17 (t,J = 6.4 Hz, 2H), 4.22- 4.25 (m, 1H), 4.29-4.34 (m, 1H), 4.67-4.72 (m,1H), 5.08-5.13 (m, 1H), 5.41-5.43 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H),7.34 (dd, J = 1.6, 8.4 Hz, 1H), 7.42 (s, 1H), 7.62 (d, J = 6.4 Hz, 2H),7.82 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 8.24 (dd, J = 2.4, 8.8 Hz, 1H),8.33 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.65 (d, J = 2.0 Hz1H), 9.36 (s, 1H), 11.10 (s, 1H). 176

C 809.5 1H NMR (400 MHz, DMSO-d6): δ 1.71-1.81 (m, 4H), 1.97-2.01 (m,1H), 2.33-2.37 (m, 2H), 2.40-2.46 (m, 2H), 2.54- 2.58 (m, 2H), 2.82-2.91(m, 1H), 3.38 (t, J = 6.4 Hz, 2H), 3.43-3.49 (m, 6H), 3.81-3.84 (m, 2H),3.94 (s, 3H), 4.16-4.25 (m, 3H), 4.43-4.48 (m, 1H), 5.01-5.06 (m, 1H),5.30- 5.36 (m, 1H), 6.61-6.64 (m, 1H), 6.77 (d, J = 1.6 Hz, 1H), 6.98(d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.69-7.72 (m, 2H), 8.05(d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 8.58 (d, J = 6.0 Hz, 1H), 9.24 (s,1H), 11.06 (s, 1H). 177

A 759.6 1H NMR (400 MHz, DMSO-d6): δ 1.71-1.80 (m, 4H), 1.90-1.93 (m,1H), 2.28-2.37 (m, 3H), 2.40-2.44 (m, 2H), 2.56- 2.57 (m, 1H), 2.83-2.92(m, 1H), 3.37 (t, J = 6.0 Hz, 2H), 3.43-3.48 (m, 6H), 3.67-3.70 (m, 2H),3.95 (s, 3H), 4.11-4.19 (m, 4H), 4.23-4.27 (m, 1H), 4.42-4.44 (m, 1H),4.99- 5.03 (m, 1H), 5.31-5.34 (m, 1H), 6.46-6.49 (m, 2H), 6.94 (d, J =8.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.60-7.63 (m, 2H), 7.97 (s, 1H),8.17-8.20 (m, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.50 (d, J = 6.0 Hz, 1H),8.64 (d, J = 2.0 Hz, 1H), 9.37 (s, 1H), 10.92 (s, 1H). 178

A 771.6 1HNMR (400 MHz, DMSO-d6): δ 1.32 (s, 4H), 1.50-1.52 (m, 4H),2.00- 2.04 (m, 1H), 2.31-2.44 (m, 5H), 2.55-2.60 (m, 1H), 2.83-2.90 (m,1H), 2.95-3.02 (m, 1H), 3.28- 3.31 (m, 2H), 3.42-3.45 (m, 2H), 3.57-3.59(m, 2H), 3.73-3.77 (m, 2H), 4.06-4.10 (m, 2H), 4.14- 4.20 (m, 4H),5.02-5.07 (m, 1H), 5.32-5.34 (m, 1H), 6.61-6.63 (m, 1H), 6.76 (s, 1H),6.96-6.99 (m, 1H), 7.59-7.61 (m, 1H), 7.85-7.87 (m, 1H), 8.20- 8.26 (m,3H), 8.52-8.55 (m, 1H), 8.70 (br, 1H), 8.76-8.78 (m, 1H), 9.77 (s, 1H),11.06 (s, 1H). 179

A 777.5 ¹H NMR (400 MHz, DMSO-d6): δ 2.02-2.08 (m, 1H), 2.55-2.73 (m,6H), 2.84-2.91 (m, 1H), 3.89-3.93 (m, 2H), 3.97 (s, 3H), 4.36-4.42 (m,2H), 4.49 (s, 2H), 5.05-5.15 (m, 2H), 5.44 (s, 1H), 7.00 (d, J = 8.8 Hz,1H), 7.30-7.33 (m, 1H), 7.37-7.40 (m, 1H), 7.45-7.49 (m, 2H), 7.63-7.67(m, 2H), 7.83 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 8.20-8.25 (m, 2H), 8.34(d, J = 8.4 Hz, 1H), 8.52 (d, J = 6.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H),9.39 (s, 1H), 11.11 (s, 1H). 180

A 705.4 ¹HNMR (400 MHz, DMSO-d6): δ 1.97-2.00 (m, 1H), 2.33-2.44 (m,2H), 2.55-2.67 (m, 4H), 2.86-2.96 (m, 1H), 4.29 (d, J = 17.2 Hz, 1H),4.42 (d, J = 16.8Hz, 1H), 5.06-5.10 (m, 2H), 5.18 (s, 2H), 5.42-5.45 (m,1H), 6.99 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.29-7.33 (m,2H), 7.50 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.74 (d, J =5.6 Hz, 1H), 7.89 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.24 (s, 1H), 8.41(d, J = 7.6 Hz, 1H), 8.53-8.59 (m, 2H), 9.56 (s, 1H), 10.97 (s, 1H),12.54 (br, 1H). 181

B 771.6 1HNMR (400 MHz, DMSO-d6): δ 1.34-1.41 (m, 2H), 1.48-1.57 (m,4H), 1.84-1.89 (m, 2H), 1.95-1.99 (m, 1H), 2.31- 2.46 (m, 5H), 2.54-2.58(m, 2H), 2.79-2.92 (m, 2H), 3.35-3.42 (m, 4H), 3.68-3.71 (m, 2H), 3.95(s, 3H), 4.11-4.19 (m, 3H), 5.01-5.05 (m, 1H), 5.29-5.35 (m, 1H), 6.59(d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 7.59-7.62(m, 3H), 7.96 (s, 1H), 8.16-8.19 (m, 1H), 8.30-8.32 (d, J = 8.0 Hz, 1H),8.49 (d, J = 8.0 Hz, 1H), 8.61-8.62 (m, 1H), 9.35 (s, 1H), 11.06 (s,1H). 182

A 759.5 1H NMR (400 MHz, DMSO-d6): δ 1.73-1.79 (m, 4H), 1.97-2.00 (m,1H), 2.33-2.45 (m, 5H), 2.54-2.58 (m, 1H), 2.82- 2.90 (m, 1H), 3.37 (t,J = 6.4 Hz, 2H), 3.43-3.49 (m, 6H), 3.81-3.84 (m, 2H), 4.16-4.20 (m,1H), 4.22- 4.26 (m, 2H), 4.43-4.47 (m, 1H), 5.02-5.06 (m, 1H), 5.31-5.34(m, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 6.93 (d, J = 8.4 Hz,1H), 7.60-7.65 (m, 2H), 7.72 (d, J = 6.0 Hz, 1H), 7.86 (s, 1H), 8.11-8.14 (m, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 6.0 Hz, 1H), 8.57(d, J = 2.0 Hz, 1H), 9.53 (s, 1H), 11.06 (s, 1H), 12.42 (s, 1H). 183

A 719.4 ¹H NMR (400 MHz, DMSO-d6): δ 2.03-2.07 (m, 1H), 2.18-2.24 (m,2H), 2.54-2.62 (m, 1H), 2.84-2.94 (m, 1H), 3.17- 3.20 (m, 3H), 4.67 (t,J = 6.4 Hz, 1H), 5.01 (t, J = 6.8 Hz, 1H), 5.11-5.15 (m, 1H), 5.32 (s,2H), 6.97 (d, J = 8.4 Hz, 1H), 7.33-7.36 (m, 1H), 7.45-7.52 (m, 2H),7.58 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 5.6 Hz,1H), 7.89 (s, 1H), 7.91 (s, 1H), 8.14-8.16 (m, 1H), 8.25 (d, J = 2.8 Hz,1H), 8.41 (d, J = 8.4 Hz, 1H), 8.54-8.55 (m, 1H), 8.58 (d, J = 2.4 Hz,1H), 9.56 (s, 1H), 11.12 (s, 1H), 12.49 (s, 1H). 184

A 795.6 1H NMR (400 Hz, D6- DMSO): δ 1.30-1.50 (m, 8H), 1.72-1.79 (m,2H), 1.84 (s, 6H), 1.97-2.06 (m, 2H), 2.56-2.67 (m, 2H), 2.84-2.93 (m,1H), 3.85- 3.88 (m, 1H), 3.99 (s, 3H), 4.13-4.18 (m, 3H), 4.21- 4.24 (m,1H), 4.29-4.33 (m, 1H), 4.67-4.71 (m, 1H), 5.09-5.13 (m, 1H), 5.41-5.45(m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.41 (s,1H), 7.66 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 5.6 Hz, 1H), 7.82 (d, J =8.4 Hz, 1H), 8.04 (s, 1H), 8.23- 8.29 (m, 1H), 8.37 (d, J = 8.0 Hz, 1H),8.55 (d, J = 5.6 Hz, 1H), 8.66 (s, 1H), 9.44 (s, 1H), 11.11 (s, 1H),.185

C 836.5 1H NMR (400 MHz, DMSO-d6): δ 0.67 (d, J = 6.8 Hz, 3H), 0.83-0.88(m, 3H), 1.97-2.02 (m, 2H), 2.31-2.33 (m, 1H), 2.46 (s, 3H), 3.51 (s,1H), 3.66- 3.72 (m, 2H), 4.22-4.26 (m, 2H), 4.34-4.42 (m, 4H), 4.49-4.51(m, 2H), 4.68 (d, J = 10.0 Hz, 1H), 5.05 (d, J = 4.4 Hz, 1H), 5.32 (t, J= 4.8 Hz, 1H), 6.58 (d, J = 9.6 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 7.06(s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.47-7.53 (m, 2H), 7.58-7.63 (m, 4H),7.69 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 7.96-7.99 (m, 1H), 8.31-8.33 (m,2H), 8.40 (m, 1H), 8.48 (d, J = 6.0 Hz, 1H), 8.98 (s, 1H), 9.45 (s, 1H).186

B 880.6 1H NMR (400 MHz, DMSO-d6): δ 0.72 (d, J = 6.8 Hz, 3H), 0.96 (d,J = 6.4 Hz, 3H), 1.89-1.96 (m, 1H), 2.02-2.08 (m, 1H), 2.28-2.34 (m,1H), 2.47 (s, 3H), 3.68-3.70 (m, 1H), 3.75-3.80 (m, 1H), 3.88- 3.92 (m,4H), 4.20-4.39 (m, 5H), 4.40-4.58 (m, 5H), 4.71 (d, J = 10.8 Hz, 1H),5.10 (d, J = 3.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 7.6 Hz,1H), 7.07 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.46-7.53 (m, 1H),7.56-7.67 (m, 4H), 7.70 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 8.11- 8.14(m, 1H), 8.36-8.40 (m, 2H), 8.50 (d, J = 6.0 Hz, 1H), 8.58 (d, J = 2.4Hz, 1H), 8.98 (s, 1H), 9.48 (s, 1H), 12.16-12.29 (m, 1H). 187

C 924.6 1H NMR (400 MHz, DMSO-d6): δ 0.71 (d, J = 6.8 Hz, 3H), 0.95 (d,J = 6.8 Hz, 3H), 1.89-2.07 (m, 3H), 2.26-2.39 (m, 2H), 2.46 (s, 3H),3.64-3.70 (m, 5H), 3.75-3.83 (m, 5H), 4.18-4.23 (m, 2H), 4.27- 4.36 (m,3H), 4.39-4.46 (m, 4H), 4.52-4.57 (m, 1H), 4.69-4.72 (m, 1H), 5.08 (d, J= 4.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.05(s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.47-7.51 (m, 1H), 7.55-7.60 (m, 4H),7.70 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 8.09- 8.11 (m, 1H), 8.31-8.34(m, 1H), 8.36-8.39 (m, 1H), 8.45 (d, J = 4.8 Hz, 1H), 8.55 (m, 1H), 8.98(s, 1H), 9.41 (s, 1H). 188

B 762.5 ¹H NMR (400 MHz, DMSO-d6): δ 2.02-2.08 (m, 1H), 2.51-2.78 (m,6H), 2.85-2.94 (m, 1H), 3.86-3.92 (m, 2H), 4.38- 4.40 (m, 2H), 4.45 (s,2H), 4.98-5.03 (m, 1H), 5.09- 5.15 (m, 1H), 5.40-5.45 (m, 1H), 6.88 (d,J = 8.8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 1H), 7.36-7.40 (m, 3H), 7.47 (d, J= 2.0 Hz, 1H), 7.61-7.67 (m, 2H), 7.82-7.85 (m, 2H), 8.14- 8.17 (m, 1H),8.37 (d, J = 8.0 Hz, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.58 (d, J = 2.4 Hz,1H), 9.48 (s, 1H), 11.12 (s, 1H), 12.22 (br, 1H). 189

B 718.4 ¹H NMR (400 MHz, DMSO-d6): δ 2.03-2.08 (m, 1H), 2.54-2.70 (m,6H), 2.84 -2.92 (m, 1H), 4.98-5.03 (m, 1H), 5.10- 5.16 (m, 1H), 5.27 (s,2H), 5.39-5.45 (m, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz,1H), 7.40 (d, J = 8.8 Hz, 2H), 7.45-7.47 (m, 1H), 7.57 (d, J = 2.0 Hz,1H), 7.65-7.70 (m, 2H), 7.86-7.91 (m, 2H), 8.14- 8.17 (m, 1H), 8.39 (d,J = 8.0 Hz, 1H), 8.52 (d, J = 6.4 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H),9.52 (s, 1H), 11.12 (s, 1H), 12.37 (s, 1H). 190

C 773.5 1H NMR (400 MHz, DMSO-d6): δ 1.84-1.89 (m, 2H), 1.95-2.03 (m,3H), 2.31-2.39 (m, 4H), 2.81-2.88 (m, 2H), 3.45- 3.55 (m, 12H), 3.68 (m,2H), 4.10 (s, 3H), 4.24 (m, 1H), 5.00-5.04 (m, 1H), 5.03 (s, 1H),6.55-6.58 (m, 1H), 6.70 (s, 1H), 6.94- 6.97 (m, 1H), 7.56-7.57 (m, 1H),7.80-7.82 (m, 1H), 8.11-8.23 (m, 3H), 8.48-8.51 (m, 1H), 8.67- 8.73 (m,2H), 9.69 (s, 1H), 11.06 (s, 1H). 191

A 773.5 1HNMR (400 MHz, DMSO-d6): δ 1.72-1.78 (m, 2H), 1.95-2.01 (m,1H), 2.31-2.46 (m, 4H), 2.54-2.67 (m, 2H), 2.82- 2.91 (m, 1H), 2.95-3.02(m, 1H), 3.44-3.52 (m, 8H), 3.58-3.60 (m, 2H), 3.73-3.76 (m, 2H), 3.97(s, 3H), 4.07 (t, J = 8.0 Hz, 2H), 4.20-4.25 (m, 1H), 5.02-5.06 (m, 1H),5.29- 5.35 (m, 1H), 6.59-6.61 (m, 1H), 6.74-6.75 (m, 1H), 6.93-6.95 (d,J = 8.0 Hz, 1H), 7.58-7.68 (m, 3H), 7.99 (s, 1H), 8.17- 8.20 (m, 1H),8.33 (d, J = 8.0 Hz, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.63-8.64 (m, 1H),9.39 (s, 1H), 11.07 (s, 1H). 192

C 759.5 1HNMR (400 MHz, DMSO-d6): δ 1.95-1.99 (m, 1H), 2.08 (s, 1H),2.31-2.37 (m, 2H), 2.41- 2.46 (m, 3H), 2.54-2.58 (m, 1H), 2.83-2.89 (m,1H), 2.96-3.01 (m, 1H), 3.44-3.46 (m, 1H), 3.53- 3.57 (m, 6H), 3.64-3.66(m, 2H), 3.74-3.78 (m, 2H), 3.95 (s, 3H), 4.08 (t, J = 8.4 Hz, 2H),4.21-4.23 (m, 1H), 5.01-5.06 (m, 1H), 5.30-5.33 (m, 1H), 6.60 (d, J =9.6 Hz, 1H), 6.75 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 7.58-7.64 (m, 3H),7.97 (s, 2H), 8.17- 8.20 (m, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.49 (d, J =5.6 Hz, 1H), 8.62-8.63 (m, 1H), 9.36 (s, 1H), 11.06 (s, 1H); 193

B 798.5 1H NMR: (400 MHz, DMSO-d6) δ: 11.07 (br s, 1H), 9.36 (s, 1H),8.66-8.58 (m, 1H), 8.49 (d, J = 5.8 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H),8.23 (s, 2H), 8.18 (dd, J = 2.5, 8.7 Hz, 1H), 7.97 (s, 1H), 7.66-7.58(m, 3H), 6.92 (d, J = 8.7 Hz, 1H), 6.81 (br d, J = 2.3 Hz, 1H),6.69-6.63 (m, 1H), 5.16- 5.08 (m, 1H), 5.08-5.02 (m, 1H), 4.47 (br s,1H), 4.30-4.22 (m, 3H), 4.19 (s, 1H), 3.99 (s, 1H), 3.95 (s, 3H),3.95-3.89 (m, 4H), 3.86 (br s, 3H), 3.49- 3.48 (m, 2H), 2.92-2.81 (m,1H), 2.74 (br d, J = 6.5 Hz, 2H), 2.58 (br s, 1H), 2.54 (s, 2H),2.30-2.26 (m, 1H), 1.98 (br d, J = 4.9 Hz, 1H), 1.85-1.74 (m, 2H). 194

C 774.5 1HNMR (400 MHz, DMSO-d6): δ 1.93-2.11 (m, 2H), 2.54-2.74 (m,5H), 2.54-2.93 (m, 1H), 3.95-3.98 (m, 2H), 4.31- 4.34 (m, 2H), 4.49 (s,3H), 4.67-4.73 (m, 1H), 5.04- 5.14 (m, 2H), 5.41-5.47 (m, 1H), 6.67-6.69(m, 1H), 6.82-6.83 (m, 1H), 6.99 (d, J = 8.0 Hz, 1H), 7.33-7.36 (m, 1H),7.53- 7.55 (m, 1H), 7.65-7.72 (m, 3H), 7.88 (s, 3H), 8.15-8.18 (m, 1H),8.25- 8.26 (m, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.52-8.54 (m, 1H),8.58-8.59 (m, 1H), 9.54 (s, 1H), 11.07 (s, 1H). 195

A 786.5 1H NMR (400 MHz, DMSO-d6): δ 2.01-2.04 (m, 1H), 2.50-2.60 (m,2H), 2.83-2.92 (m, 1H), 3.52-3.59 (m, 12H), 3.77- 3.79 (m, 4H),4.27-4.28 (m, 5H), 4.43-4.46 (m, 2H), 5.08-5.13 (m, 1H), 6.96 (d, J =8.4 Hz, 1H), 7.32-7.34 (m, 1H), 7.41 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H),7.79 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 8.19- 8.22 (m, 1H), 8.35 (d, J =8.0 Hz, 1H), 8.44 (s, 1H), 8.64-8.65 (m, 1H), 9.22 (s, 1H), 11.10 (s,1H). 196

C 968.6 1H NMR (400 MHz, DMSO-d6): δ 0.71 (d, J = 6.8 Hz, 3H), 0.95 (d,J = 6.8 Hz, 3H), 1.89-2.07 (m, 3H), 2.27-2.35 (m, 2H), 2.46 (s, 3H),3.57-3.58 (m, 5H), 3.63-3.68 (m, 4H), 3.76-3.81 (m, 5H), 4.17- 4.19 (m,2H), 4.27-4.34 (m, 3H), 4.39-4.46 (m, 4H), 4.52-4.57 (m, 1H), 4.69-4.72(m, 1H), 5.09 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz,1H), 7.04 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.47- 7.51 (m, 1H),7.60-7.64 (m, 4H), 7.70 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 8.09-8.14 (m,1H), 8.34- 8.38 (m, 2H), 8.49 (d, J = 4.8 Hz, 1H), 8.55-8.56 (m, 1H),8.97 (s, 1H), 9.47 (s, 1H). 197

C 819.5 1H NMR: (400 MHz, CDCl3) δ: 9.37 (s, 1H), 8.61 (d, J = 6.0 Hz,1H), 8.51 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.95-7.93 (m,1H), 7.64 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H),7.4 (d, J = 6.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 2.4 Hz,1H), 6.50-6.48 (m, 1H), 5.44-5.41 (m, 1H), 4.96 (dd, J = 5.2, 12.4 Hz,1H), 4.31-4.27 (m, 1H), 4.07-4.02 (m, 5H), 3.94 (s, 3H), 3.59 (t, J =12.4 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H), 2.92-2.78 (m, 3H), 2.65-2.48 (m,6H), 2.32-2.27 (m, 2H), 2.19-1.99 (m, 4H), 1.86- 1.79 (m, 1H). 198

A 815.5 1HNMR (400 MHz, CD3OD): δ 1.46-1.55 (m, 2H), 1.84-1.94 (m, 2H),2.03-2.07 (m, 1H), 2.35- 2.46 (m, 4H), 2.58-2.62 (m, 1H), 2.85-2.94 (m,3H), 3.50-3.56 (m, 3H), 3.99 (m, 3H), 4.38-4.44 (m, 1H), 5.11-5.16 (m,1H), 5.28 (s, 2H), 5.31- 5.34 (m, 1H), 6.80-6.82 (m, 1H), 6.95-7.01 (m,3H), 7.18-7.22 (m, 1H), 7.45-7.48 (m, 1H), 7.57- 7.58 (m, 1H), 7.66-7.68(m, 1H), 7.75-7.81 (m, 1H), 7.89-7.91 (m, 1H), 8.03 (s, 1H), 8.19-8.22(m, 1H), 8.36-8.66 (m, 3H), 9.42 (br, 1H), 11.12 (s, 1H). 199

C 811.6 1H NMR (400 MHz, CDCl3): δ 1.71-1.98 (m, 6H), 2.06-2.15 (m, 8H),2.46-2.57 (m, 2H), 2.57- 2.88 (m, 4H), 2.96-3.10 (m, 2H), 3.43-3.56 (m,3H), 3.94 (s, 3H), 4.05- 4.20 (m, 2H), 4.91-5.01 (m, 1H), 5.05-5.26 (m,1H), 5.31-5.42 (m, 1H), 6.82-6.94 (m, 1H), 7.14- 7.23 (m, 1H), 7.31-7.45(m, 2H), 7.48-7.65 (m, 2H), 7.73-7.81 (m, 1H), 7.89-7.99 (m, 1H), 8.19-8.28 (m, 1H), 8.38-8.67 (m, 3H), 9.32-9.42 (m, 1H). 200

A 711.6 1H NMR (400 MHz, DMSO-d6): δ 1.23 (s, 4H), 1.50-1.54 (m, 4H),1.97- 2.03 (m, 2H), 2.33-2.37 (m, 2H), 2.40-2.46 (m, 2H), 2.54-2.67 (m,2H), 2.83-2.92 (m, 2H), 3.31 (t, J = 6.4 Hz, 2H), 3.41 (t, J = 6.4 Hz,2H), 3.82-3.85 (m, 2H), 4.14 (s, 3H), 4.16- 4.26 (m, 3H), 4.43-4.48 (m,1H), 5.03-5.07 (m, 1H), 5.32-5.35 (m, 1H), 6.63-6.66 (m, 1H), 6.78 (s,1H), 6.98 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.87 (d, J =8.4 Hz, 1H), 8.20-8.26 (m, 3H), 8.53 (d, J = 8.4 Hz, 1H), 8.70 (d, J =2.0 Hz, 1H), 8.76 (d, J = 6.8 Hz, 1H), 9.76 (s, 1H), 11.07 (s, 1H). 201

C 1012.7 1H NMR (400 MHz, DMSO-d6): δ 0.72 (d, J = 6.4 Hz, 3H), 0.95 (d,J = 6.4 Hz, 3H), 1.89-1.95 (m, 1H), 2.03-2.08 (m, 1H), 2.16-2.35 (m,2H), 2.46 (s, 3H), 3.52-3.58 (m, 10H), 3.62-3.70 (m, 4H), 3.77- 3.78 (m,5H), 4.14-4.21 (m, 2H), 4.27-4.34 (m, 3H), 4.39-4.47 (m, 4H), 4.52-4.57(m, 1H), 4.70- 4.72 (m, 1H), 5.09-5.10 (m, 1H), 6.95-7.04 (m, 3H), 7.34(d, J = 8.0 Hz, 1H), 7.47-7.51 (m, 1H), 7.58- 7.62 (m, 2H), 7.65-7.73(m, 3H), 7.87 (s, 1H), 8.11-8.14 (m, 1H), 8.36- 8.40 (m, 2H), 8.53 (d, J= 6.4 Hz, 1H), 8.56-8.58 (m, 1H), 8.97 (s, 1H), 9.54 (s, 1H). 202

B 800.6 1H NMR (400 MHz, DMSO-d6): δ 1.66-1.82 (m, 3H), 1.95-2.00 (m,1H), 2.28-2.47 (m, 6H), 2.54-2.60 (m, 1H), 2.81- 2.91 (m, 4H), 2.97-3.11(m, 2H), 3.34-3.38 (m, 1H), 3.66-3.69 (m, 2H), 3.78-3.86 (m, 2H), 3.96(s, 3H), 4.07-4.11 (m, 2H), 4.19-4.23 (m, 3H), 5.00- 5.07 (m, 1H),5.29-5.35 (m, 1H), 6.58-6.64 (m, 1H), 6.73-6.78 (m, 1H), 6.91-6.96 (m,1H), 7.57- 7.67 (m, 3H), 7.95-8.00 (m, 1H), 8.15-8.21 (m, 1H), 8.29-8.35(m, 1H), 8.48-8.54 (m, 1H), 8.60- 8.66 (m, 1H), 9.38 (s, 1H), 11.05 (s,1H). 203

A 777.5 1H NMR: (400 MHz, DMSO-d6): δ: 11.13 (s, 1H), 9.37 (s, 1H), 8.96(d, J = 2.5 Hz, 1H), 8.81 (d, J = 2.5 Hz, 1H), 8.51 (d, J = 5.8 Hz, 1H),8.35 (d, J = 8.2 Hz, 1H), 8.25 (s, 1H), 8.10 (d, J = 0.9 Hz, 1H), 7.79(d, J = 8.3 Hz, 1H), 7.74-7.67 (m, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.41(d, J = 2.1 Hz, 1H), 7.33 (dd, J = 2.3, 8.3 Hz, 1H), 5.19 -5.04 (m, 1H),4.60 (dd, J = 3.9, 5.4 Hz, 2H), 4.32-4.22 (m, 2H), 3.96 (s, 3H),3.86-3.81 (m, 2H), 3.79-3.74 (m, 2H), 3.65-3.52 (m, 12H), 2.92- 2.82 (m,1H), 2.63-2.54 (m, 2H), 2.07-1.97 (m, 1H) 204

C 755.4 1H NMR (400 MHz, CDCl3): δ 1.98-2.03 (m, 2H), 2.18-2.22 (m, 2H),2.69-2.77 (m, 4H), 5.33- 5.36 (m, 1H), 5.48-5.52 (m, 1H), 6.86 (d, J =8.4 Hz, 1H), 7.05 (dd, J = 2.4, 8.4 Hz, 1H), 7.22 (d, J = 4.8 Hz, 1H),7.32 (dd, J = 2.0, 8.4 Hz, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.49 (d, J =1.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 8.20(d, J = 2.8 Hz, 1H), 8.35 (s, 1H), 8.57 (d, J = 6.0 Hz, 1H), 9.38 (s,1H). 205

A 819.6 1HNMR (400 MHz, CD3OD): δ 1.44-1.58 (m, 2H), 1.84-1.91 (m, 2H),2.04-2.07 (m, 3H), 2.34- 2.44 (m, 4H), 2.62-2.93 (m, 7H), 3.46-3.49 (m,2H), 3.99 (m, 3H), 4.14- 4.17 (m, 2H), 4.39-4.42 (m, 1H), 5.11-5.15 (m,1H), 5.32-5.34 (m, 1H), 6.63-6.64 (m, 1H), 6.75- 6.78 (m, 2H), 6.95-6.97(m, 1H), 7.09-7.13 (m, 1H), 7.36-7.38 (m, 1H), 7.43 (s, 1H), 7.66-7.73(m, 2H), 7.83-7.85 (m, 1H), 8.02 (s, 1H), 8.20-8.22 (m, 1H), 8.36-8.38(m, 1H), 8.53-8.55 (m, 1H), 8.66 (s, 1H), 9.43 (s, 1H), 11.12 (s, 1H).206

B 803.6 1HNMR (400 MHz, DMSO-d6): δ 1.97-2.00 (m, 1H), 2.32-2.37 (m,2H), 2.42-2.46 (m, 2H), 2.54-2.58 (m, 2H), 2.82- 2.91 (m, 1H), 2.95-3.01(m, 1H), 3.44-3.46 (m, 2H), 3.53-3.56 (m, 10H), 3.62-3.64 (m, 2H), 3.72-3.75 (m, 2H), 4.02 (s, 3H), 4.06 (t, J = 8.0 Hz, 2H), 4.20-4.24 (m, 1H),5.02- 5.06 (m, 1H), 5.29-5.34 (m, 1H), 6.58-6.60 (m, 1H), 6.73-6.75 (m,1H), 6.95 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.69 (d, J =8.0 Hz, 1H), 7.82-7.84 (m, 1H), 8.06 (s, 1H), 8.19-8.22 (m, 1H), 8.39(d, J = 8.0 Hz, 1H), 8.58-8.59 (m, 1H), 8.65- 8.66 (m, 1H), 9.49 (s,1H), 11.07 (s, 1H). 207

B 739.5 1H NMR (400 MHz, DMSO-d6): δ: 11.13 (s, 1H), 9.57 (d, J = 7.2Hz, 1H), 9.13 (d, J = 2.4 Hz, 1H), 8.63 (dd, J = 2.5, 8.8 Hz, 1H), 8.31(d, J = 8.2 Hz, 1H), 7.87-7.77 (m, 3H), 7.59-7.48 (m, 1H), 7.45-7.39 (m,2H), 7.35 (dd, J = 2.3, 8.3 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 5.11 (dd,J = 5.3, 12.8 Hz, 1H), 4.53-4.48 (m, 2H), 4.32-4.27 (m, 2H), 3.81- 3.76(m, 4H), 3.62-3.58 (m, 4H), 3.55 (dd, J = 2.8, 5.5 Hz, 4H), 3.52 (s,4H), 2.94-2.84 (m, 1H), 2.65- 2.54 (m, 2H), 2.09-2.00 (m, 1H). 208

A 763.5 1H NMR (400 MHz, DMSO-d6): δ 1.99-2.06 (m, 1H), 2.52-2.61 (m,2H), 2.83-2.92 (m, 1H), 3.52-3.63 (m, 12H), 3.76- 3.84 (m, 4H), 3.97 (s,3H), 4.19-4.23 (m, 2H), 4.26- 4.32 (m, 2H), 4.45-.50 (m, 1H), 5.08-5.13(m, 1H), 6.52 (d, J = 8.8 Hz, 1H), 7.33-7.35 (m, 1H), 7.43 (d, J = 2.0Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 6.0 Hz, 1H), 7.80 (d, J= 8.4 Hz, 1H), 7.92 (s, 1H), 8.00-8.03 (m, 1H), 8.31 (d, J = 8.4 Hz,1H), 8.52 (d, J = 6.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 9.40 (s, 1H),11.11 (s, 1H). 209

A 800.5 1H NMR (400 MHz, CDCl3): δ 1.70 (s, 6H), 2.12-2.18 (m, 1H),2.48- 2.59 (m, 4H), 2.76-2.84 (m, 2H), 2.86-2.93 (m, 1H), 3.39 (s, 2H),3.52 (s, 2H), 3.67-3.69 (m, 2H), 3.72-3.75 (m, 2H), 3.91- 3.94 (m, 2H),4.12 (s, 3H), 4.28-4.36 (m, 4H), 4.93- 4.99 (m, 1H), 6.99 (d, J = 8.8Hz, 1H), 7.19-7.24 (m, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.70-7.82 (m, 4H),8.16-8.19 (m, 2H), 8.40 (d, J = 8. Hz, 1H), 8.70-8.72 (m, 2H), 9.61 (s,1H). 210

C 757.6 1H NMR (400 MHz, DMSO-d6): δ: 15.03 (br s, 1H), 11.18-10.95 (m,2H), 9.55 (s, 1H), 8.64 (br d, J = 6.5 Hz, 1H), 8.30 (br d, J = 8.3 Hz,1H), 8.09 (br d, J = 6.9 Hz, 1H), 7.81 (br d, J = 8.5 Hz, 1H), 7.48-7.23 (m, 4H), 5.11 (br dd, J = 5.0, 12.7 Hz, 1H), 4.30 (br s, 2H), 4.11(br d, J = 13.1 Hz, 2H), 4.02 (s, 3H), 3.78 (br s, 2H), 3.70- 3.48 (m,18H), 3.19 (br s, 3H), 2.96-2.82 (m, 1H), 2.62-2.55 (m, 3H), 2.04 (br s,3H). 211

C 784.6 1H NMR (400 MHz, CDCl3): δ: 9.33 (s, 1H), 8.59 (d, J = 5.6 Hz,1H), 8.47 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 7.92 (dd, J =2.3, 8.3 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J =8.0 Hz, 1H), 7.34 (d, J = 6.0 Hz, 1H), 6.86-6.77 (m, 2H), 6.55 (br d, J= 6.8 Hz, 1H), 5.17 (quin, J = 6.9 Hz, 1H), 4.93 (dd, J = 5.1, 12.0 Hz,1H), 4.49 (br s, 1H), 4.25 (br t, J = 7.5 Hz, 2H), 3.96-3.84 (m, 5H),3.57-3.35 (m, 10H), 2.93-2.66 (m, 7H), 2.39- 2.27 (m, 2H), 2.16-2.08 (m,1H), 1.93-1.82 (m, 2H). 212

A 769.5 1H NMR (400 MHz, CDCl3): δ: 9.39 (s, 1H), 8.61 (d, J = 6.0 Hz,1H), 8.52-8.43 (m, 2H), 8.32- 8.04 (m, 2H), 7.93 (dd, J = 2.6, 8.6 Hz,1H), 7.63 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.53 (dd, J = 1.4, 8.1 Hz,1H), 7.42 (d, J = 6.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.78 (d, J =2.0 Hz, 1H), 6.52 (dd, J = 2.1, 8.3 Hz, 1H), 5.46-5.35 (m, 1H), 4.93(dd, J = 5.2, 12.4 Hz, 1H), 4.61-4.43 (m, 2H), 4.29-4.27 (m, 2H),4.27-4.21 (m, 2H), 4.20- 4.16 (m, 2H), 4.00-3.89 (m, 5H), 3.78-3.63 (m,4H), 2.92-2.67 (m, 3H), 2.64-2.55 (m, 2H), 2.51 (td, J = 3.5, 7.0 Hz,2H), 2.16-2.08 (m, 1H). 213

C 785.5 1H NMR (400 MHz, CDCl3): δ: 9.38 (s, 1H), 8.59 (d, J = 5.9 Hz,1H), 8.48 (d, J = 2.3 Hz, 2H), 8.22 (d, J = 8.0 Hz, 1H), 7.92 (dd, J =2.6, 8.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.49 (dd, J = 1.3, 8.1 Hz, 1H),7.40 (d, J = 6.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 2.0 Hz,1H), 6.45 (dd, J = 2.1, 8.3 Hz, 1H), 5.47-5.35 (m, 1H), 4.92 (dd, J =5.3, 12.2 Hz, 1H), 4.39-4.27 (m, 1H), 4.07-3.95 (m, 5H), 3.93 (s, 3H),3.72-3.64 (m, 4H), 3.57 (ddd, J = 3.7, 5.8, 11.9 Hz, 4H), 2.91-2.76 (m,3H), 2.59 (ddd, J = 4.0, 6.9, 13.4 Hz, 4H), 2.52-2.43 (m, 2H), 2.32-2.23(m, 2H), 2.16- 2.07 (m, 1H). 214

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*Each compound was tested at 300 nM, 100 nM, 33 nM, and 11 nM asdescribed below. The highest amount of degradation observed at anydosage for each compound is capture in Table 2 as follows: A: ≤50% tauprotein remaining after 72 hours of incubation with the test compound;B: ≤80% and >50% tau protein remaining after 72 hours of incubation withthe test compound; C: >80% tau protein remaining after 72 hours ofincubation with the test compound.

Tau Protein In Vitro Degradation Assay

To determine effect of PROTACs on tau protein degradation SK—N—SH cellswere seeded in a 24-well tissue culture-treated plate for at least18-hours prior to compound addition. Tau PROTACs were evaluated for taudegradation by lysing the cells in lysis buffer with protease inhibitorsfollowing a 72-hour incubation with tau PROTACs at 1000 nM, 300 nM and100 nM for Table 1 and 300 nM, 100 nM, 33 nM and 11 nM for Table 2. Celllysates were run on standard SDS-PAGE gels, and tau levels were detectedby Western blotting using Tau-13 antibody from Abcam (Cambridge, UK)that binds to all forms of human tau. The highest amount of degradationobserved at any dosage for each compound is shown in Tables 1 and 2above.

Tau Protein In Vivo Degradation

In the study 21 male BI6 wildtype mice, divided into seven groups ofthree mice, were treated single time via a bilateral intrahippocampalinjection with vehicle ECP-1 ([5% EtOH and 5% Cremophore RH40 in pH 7.4phosphate buffer]; group A; see the FIGURE) or Compound 4 tau PROTAC ([3μL of 1 mg/mL solution in ECP-1]; groups B to G; see the FIGURE). Allanimals were sacrificed at certain time points after the test item orvehicle injection as shown in the FIGURE, and brain samples werecollected. The hippocampus was resected, and levels of total tau weremeasured with Meso Scale Discovery assay kit. Results are presented inthe FIGURE.

Specific Embodiments

An aspect of the present disclosure provides a bifunctional compoundhaving the chemical structure:

ULM-L-PTM,

-   -   or a pharmaceutically acceptable salt, enantiomer, stereoisomer,        solvate, polymorph or prodrug thereof,    -   wherein:        -   the ULM is a small molecule E3 ubiquitin ligase binding            moiety that binds an E3 ubiquitin ligase;        -   the PTM is a Tau protein targeting moiety; and        -   the L is a bond or a chemical linking moiety connecting ULM            and PTM.

In any aspect or embodiment described herein, the E3 ubiquitin ligasebinding moiety that targets a E3 ubiquitin ligase selected from thegroup consisting of Von Hippel-Lindau (VLM) and cereblon (CLM).

In any aspect or embodiment described herein, the PTM is represented byFormula I, II, III, IV, V, VI, VII, VIII, IX, X, or XI:

wherein:

-   -   A, B, C, D, E, and F are independently selected from an        optionally substituted 5- or 6-membered aryl or heteroaryl ring,        an optionally substituted 4- to 7-membered cycloalkyl or a        heterocycloalkyl, where contact between circles indicates ring        fusion; and    -   L_(PTM) is selected from a bond, an alkyl, an alkenyl or an        alkynyl, optionally interrupted by one or more rings (i.e.,        cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or        more functional groups selected from the groups —O—, —S—, —NR¹        _(PTM)— (where R¹ _(PTM) is selected from H or alkyl), —N═N—,        —S(O)—, —SO₂—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO₂—, —NHC(O)NH—,        —NHC(O)O—, or —OC(O)NH—, wherein the said functional group is        optionally located at either end of the linker.

In any aspect or embodiment described herein, at least one of A, B, C,F, or a combination thereof is selected from optionally substituted 5-or 6-membered aryl or heteroaryl rings.

In any aspect or embodiment described herein, the rings (e.g., aryl andheteroaryl rings) of A, B, C, D and E of PTM are optionally substitutedwith 1-8 substituents each independently selected from alkyl, alkenyl,haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino,dialkylamino, acylamino, trifluoromethyl and cyano, wherein the saidalkyl and alkenyl groups are further optionally substituted.

In any aspect or embodiment described herein, the PTM is Formula I and:

-   -   A, B and C rings are independently 5- or 6-membered fused aryl        or heteroaryl rings;    -   L_(PTM) is selected from a bond or an alkyl; and    -   D is selected from a 6-membered aryl, heteroaryl or        heterocycloalkyl,    -   wherein A, B, C and D are optionally substituted with alkyl,        haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino,        dialkylamino, trifluoromethyl or cyano.

In any aspect or embodiment described herein, the PTM is Formula I and:

-   -   A and C are a phenyl or a 6-membered heteroaryl ring;    -   B is a 5-membered heteroaryl ring;    -   L_(PTM) is a bond; and    -   D is a 6-membered heteroaryl or a 6-membered heterocycloalkyl        ring,    -   wherein each A, B, C and D is optionally independently        substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy,        amino, dialkylamino, trifluoromethyl, or cyano, and wherein a        nitrogen atom of any of the A, B, C and D rings is not directly        connected to a heteroatom or to a carbon atom, to which another        heteroatom is directly attached.

In any aspect or embodiment described herein, the PTM is Formula III orIV and:

-   -   A, B and C are 5- or 6-membered fused aryl or heteroaryl rings;    -   L_(PTM) is selected from a bond or an alkyl; and    -   D and E are 5- or 6-membered fused aryl or heteroaryl rings;    -   wherein A, B, C, D and E are optionally substituted with alkyl,        haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino,        dialkylamino, trifluoromethyl, or cyano.

In any aspect or embodiment described herein, the PTM is represented bya chemical structure selected from the group consisting of:

wherein:

-   -   R¹, R² and R³ are independently selected from H, methyl, ethyl,        2-fluoroethyl and 2,2,2-trifluoroethyl;    -   R⁴ and R⁵ are independently selected from H, methyl, ethyl and        halogen; and    -   R⁶ is 1 to 2 substituents independently selected from H, methyl,        ethyl and halogen.

In any aspect or embodiment described herein, the PTM is represented bya chemical structure selected from the group consisting of:

wherein:

-   -   R¹, R² and R³ are independently selected from H, optionally        substituted alkyl, methyl, ethyl, 2-fluoroethyl and        2,2,2-trifluoroethyl; and    -   R⁷, R⁸, R⁹ and R¹⁰ are 1 to 8 substituents independently        selected from H, optionally substituted alkyl, haloalkyl,        halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino,        trifluoromethyl, or cyano.

In any aspect or embodiment described herein, the PTM is represented bya chemical structure selected from the group consisting of:

In any aspect or embodiment described herein, the ULM is a VonHippel-Lindau (VHL) ligase-binding moiety (VLM) represented by thestructure:

wherein:

-   -   X¹, X² are each independently selected from the group of a bond,        O, NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and SO₂;    -   R^(Y3), R^(Y4) are each independently selected from the group of        H, linear or branched C₁₋₆ alkyl, optionally substituted by 1 or        more halo, C₁₋₆ alkoxyl);    -   R^(P) is 1, 2, or 3 groups, each independently selected from the        group H, halo, —OH, C₁₋₃ alkyl;    -   W³ is selected from the group of an optionally substituted        -T-N(R^(1a)R^(1b)), an optionally substituted        -T-N(R^(1a)R^(1b))X³, -T-Aryl, an optionally substituted        -T-Heteroaryl, an optionally substituted -T-Heterocycle, an        optionally substituted —NR¹-T-Aryl, an optionally substituted        —NR¹-T-Heteroaryl or an optionally substituted        —NR¹-T-Heterocycle;    -   X³ is C═O, R¹, R^(1a), R^(1b);    -   R, R^(1a), R^(1b) are each independently selected from the group        consisting of H, linear or branched C₁-C₆ alkyl group optionally        substituted by 1 or more halo or —OH groups, R^(Y3)C═O,        R^(Y3)C═S, R^(Y3)SO, R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O,        N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO, and N(R^(Y3)R^(Y4))SO₂;    -   T is selected from the group of an optionally substituted alkyl,        —(CH₂)_(n)— group, wherein each one of the methylene groups is        optionally substituted with one or two substituents selected        from the group of halogen, methyl, a linear or branched C₁-C₆        alkyl group optionally substituted by 1 or more halogen or —OH        groups or an amino acid side chain optionally substituted;    -   n is 0 to 6;    -   W⁴ is

-   -   R_(14a), R_(14b), are each independently selected from the group        of H, haloalkyl, or optionally substituted alkyl;    -   W⁵ is selected from the group of a phenyl or a 5-10 membered        heteroaryl; and    -   R₁₅ is selected from the group of H, halogen, CN, OH, NO₂, N        R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),        SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionally substituted        alkyl, optionally substituted haloalkyl, optionally substituted        haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl,    -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM.

In any aspect or embodiment described herein, the ULM is a VonHippel-Lindau (VHL) ligase-binding moiety (VLM) represented by thestructure:

wherein:

-   -   W³ is selected from the group of an optionally substituted aryl,        optionally substituted heteroaryl, or

-   -   R₉ and R₁₀ are independently hydrogen, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl,        or R₉, R₁₀, and the carbon atom to which they are attached form        an optionally substituted cycloalkyl;    -   R₁₁ is selected from the group of an optionally substituted        heterocyclic, optionally substituted alkoxy, optionally        substituted heteroaryl, optionally substituted aryl,

-   -   R₁₂ is selected from the group of H or optionally substituted        alkyl;    -   R₁₃ is selected from the group of H, optionally substituted        alkyl, optionally substituted alkylcarbonyl, optionally        substituted (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl;    -   R_(14a), R_(14b), are each independently selected from the group        of H, haloalkyl, or optionally substituted alkyl;    -   W⁵ is selected from the group of a phenyl or a 5-10 membered        heteroaryl;    -   R₁₅ is selected from the group of H, halogen, CN, OH, NO₂, N        R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),        SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionally substituted        alkyl, optionally substituted haloalkyl, optionally substituted        haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl        (each independently optionally substituted);    -   R₁₆ is independently selected from the group of H, halo,        optionally substituted alkyl, optionally substituted haloalkyl,        hydroxy, or optionally substituted haloalkoxy;    -   o is 0, 1, 2, 3, or 4;    -   R₁₈ is independently selected from the group of halo, optionally        substituted alkoxy, cyano, optionally substituted alkyl,        haloalkyl, haloalkoxy or a linker; and    -   p is 0, 1, 2, 3, or 4, and wherein the dashed line indicates the        site of attachment of at least one PTM, another ULM (ULM′) or a        chemical linker moiety coupling at least one PTM or a ULM′ or        both to ULM.

In any aspect or embodiment described herein, the ULM has a chemicalstructure selected from the group of:

wherein:

-   -   R₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted        alkyl, optionally substituted hydroxyalkyl, optionally        substituted heteroaryl, or haloalkyl;    -   R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,        fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R₁₅ is selected from the group consisting of H, halogen, CN, OH,        NO₂, optionally substituted heteroaryl, optionally substituted        aryl; optionally substituted alkyl, optionally substituted        haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or        cycloheteroalkyl;    -   X is C, CH₂, or C═O; and    -   R₃ is a bond or an optionally substituted 5 or 6 membered        heteroaryl,    -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM.

In any aspect or embodiment described herein, the ULM comprises a groupaccording to the chemical structure:

wherein:

-   -   R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,        fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R⁹ is H;    -   R₁₀ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, or cyclohexyl;    -   R₁₁ is

-   -   or optionally substituted heteroaryl;    -   p is 0, 1, 2, 3, or 4;    -   each R₁₈ is independently halo, optionally substituted alkoxy,        cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a        linker;    -   R₁₂ is H, C═O;    -   R₁₃ is H, optionally substituted alkyl, optionally substituted        alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl,        optionally substituted aralkylcarbonyl, optionally substituted        arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or        optionally substituted aralkyl; and    -   R₁₅ is selected from the group consisting of H, halogen, Cl, CN,        OH, NO₂, optionally substituted heteroaryl, optionally        substituted aryl;

-   -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM.

In any aspect or embodiment described herein, the ULM comprises a groupselected from the structure consisting of:

wherein the phenyl ring in ULM-a1 through ULM-a15, ULM-b1 throughULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 is optionallysubstituted with fluorine, lower alkyl and alkoxy groups, and whereinthe dashed line indicates the site of attachment of at least one PTM,another ULM (ULM′) or a chemical linker moiety coupling at least one PTMor a ULM′ or both to ULM-a.

In any aspect or embodiment described herein, the ULM is a cereblonligase-binding moiety (CLM) that is a thalidomide, lenalidomide,pomalidomide, analogs thereof, isosteres thereof, or derivativesthereof.

In any aspect or embodiment described herein, the CLM has a chemicalstructure represented by:

wherein:

-   -   W is selected from the group consisting of CH₂, CHR, C═O, SO₂,        NH, and N-alkyl;    -   each X is independently selected from the group consisting of O,        S, and H₂;    -   Y is selected from the group consisting of CH₂, —C═CR′, NH,        N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and        S;    -   Z is selected from the group consisting of O, S, and H₂;    -   G and G′ are independently selected from the group consisting of        H, alkyl (linear, branched, optionally substituted with R′), OH,        R′OCOOR, R′OCONRR″, CH₂-heterocyclyl optionally substituted with        R′, and benzyl optionally substituted with R′;    -   Q₁, Q₂, Q₃, and Q₄ represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   A is independently selected from the group H, alkyl, cycloalkyl,        Cl and F;    -   R comprises —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″,        —CR′R″—, —CR′NR′R″—, -aryl, -hetaryl, -alkyl (linear, branched,        optionally substituted), -cycloalkyl, -heterocyclyl,        —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F,        —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″,        —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″,        —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′, —C(C═N—OR′)R″,        —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ or —OCF₃;    -   R′ and R″ are independently selected from the group consisting        of a bond, H, N, N-oxide, alkyl (linear, branched), cycloalkyl,        aryl, heteroaryl, heterocyclic, —C(═O)R, or heterocyclyl, each        of which is optionally substituted;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   R_(n) comprises a functional group or an atom,    -   wherein n is an integer from 1-4, and wherein    -   when n is 1, R_(n) is modified to be covalently joined to the        linker group (L), and    -   when n is 2, 3, or 4, then one R_(n) is modified to be        covalently joined to the linker group (L), and any other R_(n)        is optionally modified to be covalently joined to a PTM, a CLM,        a second CLM having the same chemical structure as the CLM, a        CLM′, a second linker, or any multiple or combination thereof.

In any aspect or embodiment described herein, the CLM has a chemicalstructure represented by:

wherein:

-   -   W is independently selected from the group CH₂, C═O, NH, and        N-alkyl;    -   R is independently selected from a H, methyl, alkyl;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   Rn comprises 1-4 independently selected functional groups or        atoms, and optionally, one of which is modified to be covalently        joined to a PTM, a chemical linker group (L), a CLM (or CLM′) or        combination thereof.

In any aspect or embodiment described herein, the CLM has a chemicalstructure represented by:

wherein the dashed lines indicate linker attachment points.

In any aspect or embodiment described herein, the linker (L) comprises achemical structural unit represented by the formula:

-(A)_(q)-,

wherein:

-   -   A is a group which is connected to the ULM or the PTM moiety;        and    -   q is an integer greater than or equal to 1,    -   wherein A is selected from the group consisting of, a bond,        CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3), SO₂NR^(L3), SONR^(L3),        CONR^(L3), NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO,        CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1),        NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4),        C₃₋₁₁cycloalkyl optionally substituted with 0-6 R^(L1) and/or        R^(L2) groups, C₃₋₁₁heterocyclyl optionally substituted with 0-6        R^(L1) and/or R^(L2) groups, aryl optionally substituted with        0-6 R^(L1) and/or R^(L2) groups, heteroaryl optionally        substituted with 0-6 R^(L1) and/or R^(L2) groups, where R^(L1)        or R^(L2), each independently are optionally linked to other        groups to form cycloalkyl and/or heterocyclyl moiety, optionally        substituted with 0-4 R^(L5) groups;    -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl,        NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈cycloalkyl, SC₁₋₈cycloalkyl,        NHC₁₋₈cycloalkyl, N(C₁₋₈cycloalkyl)₂,        N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH, SO₂C₁₋₈alkyl,        P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈alkyl,        CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),        C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃,        Si(OH)(C₁₋₈alkyl)₂, COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂,        CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl,        SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂,        N(C₁₋₈alkyl)CONH(C₁₋₈alkyl), N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂,        NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈ alkyl)₂, NHCONH₂,        N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NH        SO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.

In any aspect or embodiment described herein, the linker (L) comprises agroup represented by a general structure selected from the groupconsisting of:

—N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,—O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,—O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—;

wherein each m, n, o, p, q, and r, is independently 0, 1, 2, 3, 4, 5, 6,with the proviso that when the number is zero, there is no N—O or O—Obond; R is selected from the group H, methyl or ethyl, and X is selectedfrom the group H or F;

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each n and m is independently 0, 1, 2, 3, 4, 5, or 6.

In any aspect or embodiment described herein, the L comprises thefollowing chemical structure:

wherein:

-   -   W^(L1) and W^(L2) are each independently a 4-8 membered ring        with 0-4 heteroatoms, optionally substituted with RQ, each RQ is        independently a H, halo, OH, CN, CF3, C1-C6 alkyl (linear,        branched, optionally substituted), C1-C6 alkoxy (linear,        branched, optionally substituted), or 2 RQ groups taken together        with the atom they are attached to, form a 4-8 membered ring        system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C1-C6 alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; or C1-C6 alkoxy (linear, branched,        optionally substituted); and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In any aspect or embodiment described herein, L comprises the followingchemical structure:

wherein:

-   -   W^(L1) and W^(L2) are each independently aryl, heteroaryl,        cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl,        biheteroaryl, or biheterocyclic, each optionally substituted        with R^(Q), each R^(Q) is independently a H, halo, OH, CN, CF₃,        hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), OC₁₋₃alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 4-8 membered ring system        containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, NR^(YL1), O, S, NR^(YL2),        CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   Q^(L) is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally bridged, optionally substituted with 0-6        R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), or 2 R^(Q) groups taken together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   R^(YL1), R^(YL2) are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In any aspect or embodiment described herein, the L is a polyethylenoxygroup optionally substituted with aryl or phenyl comprising from 1 to 10ethylene glycol units.

In any aspect or embodiment described herein, the compound comprisesmultiple ULMs, multiple PTMs, multiple linkers or any combinationsthereof.

In any aspect or embodiment described herein, the compound is selectedfrom the group consisting of Compounds 1-330 (Table 1 or Table 2).

In any aspect or embodiment described herein, the compound is selectedfrom Table 1 or Table 2 (i.e., from compounds 1-330).

In any aspect or embodiment described herein, the compound has achemical structure selected from Formulas CI through CV:

wherein:

-   -   R¹⁰¹ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl or cyano;    -   R¹⁰² is selected from H, alkyl, haloalkyl, cycloalkyl or        heterocycloalkyl;    -   R¹⁰³ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl or cyano;    -   R¹⁰⁴ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl or cyano;    -   R¹⁰⁵ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl or cyano;    -   R¹⁰⁶, R¹⁰⁷, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, R¹¹⁴, R¹¹⁶, R¹¹⁷,        R¹²⁰, R¹²¹, R¹²⁶, R¹²⁷, R¹²² and R¹²³ are each independently        selected from H, alkyl, halogen or haloalkyl;    -   R¹⁰⁸ is 1-2 substituents independently selected from H, alkyl,        halogen, haloalkyl, cyano or methoxy;    -   R¹¹⁵ is selected from H, alkyl and haloalkyl;    -   R¹¹⁸ and R¹¹⁹ are independently selected from H, alkyl, halogen        or haloalkyl, or R¹¹⁸ and R¹¹⁹ taken together with the carbon        atom to which they are attached represent a 3-6-membered        cycloalkyl or heterocycloalkyl ring, such as cyclopropane or an        oxetane;    -   R¹²⁴ and R¹²⁵ are independently selected from H, alkyl, halogen        or haloalkyl, or R¹²⁴ and R¹²⁵ taken together with the carbon        atom to which they are attached represent a 3-6-membered        cycloalkyl or heterocycloalkyl ring, such as cyclopropane or an        oxetane;    -   G is a phenyl or a 5- or 6-membered heteroaryl ring; and    -   Z is CH₂ or C═O.

A further aspect of the disclosure provides a composition comprising aneffective amount of a bifunctional compound of the present disclosure,and a pharmaceutically acceptable carrier.

In any aspect or embodiment described herein, the composition furthercomprises at least one of additional bioactive agent, anotherbifunctional compound of any of claims 1-29, or a combination thereof.

In any aspect or embodiment described herein, the additional bioactiveagent is an anti-neurodegenerative agent.

In any aspect or embodiment described herein, the additional bioactiveagent is a P-gp inhibitor.

In any aspect or embodiment described herein, the P-gp inhibitor isAmiodarone, Azithromycin, Captopril, Clarithromycin, Cyclosporine,Piperine, Quercetin, Quinidine, Quinine, Reserpine, Ritonavir,Tariquidar, Elacridar or Verapamil.

Another aspect of the disclosure provides a composition comprising apharmaceutically acceptable carrier and an effective amount of at leastone compound of the present disclosure for treating a disease ordisorder in a subject, the method comprising administering thecomposition to a subject in need thereof, wherein the compound iseffective in treating or ameliorating at least one symptom of thedisease or disorder.

In any aspect or embodiment described herein, the disease or disorder isassociated with Tau accumulation and aggregation.

In any aspect or embodiment described herein, the disease or disorder isa neurodegenerative disease associated with Tau accumulation andaggregation.

In any aspect or embodiment described herein, the disease or disorder isAcquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis,ADHD, Adie's Pupil, Adie's Syndrome, Adrenoleukodystrophy, Agenesis ofthe Corpus Callosum, Agnosia, Aicardi Syndrome, AIDS—NeurologicalComplications, Alexander Disease, Alpers' Disease, AlternatingHemiplegia, Alzheimer's Disease, Amyotrophic Lateral Sclerosis,Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Aphasia,Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari Malformation,Arteriovenous Malformation, Asperger Syndrome, Ataxia, Ataxia,Telangiectasia, Ataxias and Cerebellar/Spinocerebellar Degeneration,Attention Deficit-Hyperactivity Disorder, Autism, Autonomic Dysfunction,Back Pain, Barth Syndrome Batten Disease, Becker's Myotonia, Behcet'sDisease, Bell's Palsy, Benign Essential Blepharospasm, Benign FocalAmyotrophy, Benign Intracranial Hypertension, Bernhardt-Roth Syndrome,Binswanger's Disease, Blepharospasm, Bloch-Sulzberger Syndrome, BrachialPlexus Birth Injuries, Brachial Plexus Injuries, Bradbury-EgglestonSyndrome, Brain and Spinal Tumors, Brain Aneurysm, Brain Injury,Brown-Sequard Syndrome, Bulbospinal Muscular Atrophy, Canavan Disease,Carpal Tunnel Syndrome Causalgia, Cavernomas, Cavernous Angioma,Cavernous Malformation, Central Cervical Cord Syndrome, Central CordSyndrome, Central Pain Syndrome, Cephalic Disorders, CerebellarDegeneration, Cerebellar Hypoplasia, Cerebral Aneurysm, CerebralArteriosclerosis, Cerebral Atrophy, Cerebral Beriberi, CerebralGigantism, Cerebral Hypoxia, Cerebral Patsy,Cerebro-Oculo-Facio-Skeletal Syndrome, Charcot-Marie-Tooth Disease,Chiari Malformation, Chorea, Choreoacanthocytosis, Chronic InflammatoryDemyelinating Polyneuropathy (CIDP), Chronic Orthostatic Intolerance,Chronic Pain Cockayne Syndrome Type II, Coffin Lowry Syndrome, COFS,Colpocephaly, Coma and Persistent Vegetative State, Complex RegionalPain Syndrome, Congenital Facial Diplegia, Congenital Myasthenia,Congenital Myopathy, Congenital Vascular Cavernous, Malformations,Corticobasal Degeneration, Cranial Arteritis, Craniosynostosis,Creutzfeldt-Jakob Disease, Cumulative Trauma Disorders, Cushing'sSyndrome, Cytomegalic Inclusion Body Disease, Cytomegalovirus Infection,Dancing Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome, DawsonDisease, De Morsier's Syndrome, Deep Brain Stimulation for Parkinson'sDisease, Dejerine-Klumpke Palsy, Dementia, Dementia—Multi-Infarct,Dementia—Semantic, Dementia—Subcortical, Dementia With Lewy Bodies,Dentate Cerebellar Ataxia, Dentatorubral Atrophy, Dermatomyositis,Developmental Dyspraxia, Devic's Syndrome, Diabetic Neuropathy, DiffuseSclerosis, Dysautonomia, Dysgraphia, Dyslexia, Dysphagia, Dyspraxia,Dyssynergia Cerebellaris, Myoclonica, Dyssynergia CerebellarisProgressiva, Dystonias, Early Infantile Epileptic, Encephalopathy, EmptySella Syndrome, Encephalitis Lethargica, Encephaloceles, Encephalopathy,Encephalotrigeminal Angiomatosis, Epilepsy, Erb-Duchenne andDejerine-Klumpke Palsies, Erb's Palsy, Fabry's Disease, Fahr's Syndrome,Fainting, Familial Dysautonomia, Familial Hemangioma, FamilialIdiopathic Basal Ganglia, Calcification, Familial Periodic Paralyses,Familial Spastic Paralysis, Febrile Seizures, Fisher Syndrome, FloppyInfant Syndrome, Friedreich's Ataxia, Frontotemporal, Dementia,Gaucher's Disease, Gerstmann's Syndrome, Gerstmann-Straussler-Scheinker,Disease, Giant Cell Arteritis, Giant Cell Inclusion Disease, GloboidCell Leukodystrophy, Glossopharyngeal Neuralgia, Guillain-BarreSyndrome, Hallervorden-Spatz Disease, Head Injury, Headache, HemicraniaContinua, Hemifacial Spasm, Hemiplegia Alterans, HereditaryNeuropathies, Hereditary Spastic Paraplegia, Heredopathia AtacticaPolyneuritiformis, Herpes Zoster, Herpes Zoster Oticus, HirayamaSyndrome, Holmes-Adie syndrome, Holoprosencephaly, HTLV-1 Associated,Myelopathy, Huntington's Disease, Hydranencephaly, Hydrocephalus,Hydrocephalus—Normal Pressure, Hydromyelia, Hyperactivity,Hypercortisolism, Hypersomnia, Hypertonia, Hypotonia,—Infantile,Hypoxia, Immune-Mediated Encephalomyelitis, Inclusion Body Myositis,Incontinentia Pigmenti, Infantile Hypotonia, Infantile NeuroaxonalDystrophy, Infantile Phytanic Acid Storage Disease, Infantile RefsumDisease, Infantile Spasms, Inflammatory Myopathy, Iniencephaly,Intestinal Lipodystrophy, Intracranial Cysts, Intracranial Hypertension,Isaac's Syndrome, Joubert Syndrome, Kearns-Sayre Syndrome, Kennedy'sDisease, Kinsbourne syndrome, Kleine-Levin Syndrome, Klippel-FeilSyndrome, Klippel-Trenaunay Syndrome (KTS), Klüver-Bucy Syndrome,Korsakoff's Amnesic Syndrome, Krabbe Disease, Kugelberg-WelanderDisease, Kuru, Lambert-Eaton Myasthenic Syndrome, Landau-KleffnerSyndrome, Lateral Femoral, Cutaneous Nerve Entrapment, Lateral MedullarySyndrome, Learning Disabilities, Leigh's Disease, Lennox-GastautSyndrome, Lesch-Nyhan Syndrome, Leukodystrophy, Levine-CritchleySyndrome, Lewy Body Dementia, Lipid Storage Diseases, Lissencephaly,Locked-In Syndrome, Lou Gehrig's Disease, Lupus—Neurological, Sequelae,Lyme Disease—Neurological Complications, Machado-Joseph Disease,Macrencephaly, Mania, Megalencephaly, Melkersson-Rosenthal Syndrome,Meningitis, Meningitis and Encephalitis, Menkes Disease, MeralgiaParesthetica, Metachromatic, Leukodystrophy, Microcephaly, Migraine,Miller Fisher Syndrome, Mini-Strokes, Mitochondrial Myopathies, MobiusSyndrome, Monomelic Amyotrophy, Motor Neuron Diseases, Moyamoya Disease,Mucolipidoses, Mucopolysaccharidoses, Multifocal Motor Neuropathy,Multi-Infarct Dementia, Multiple Sclerosis, Multiple System Atrophy,Multiple System Atrophy with Orthostatic Hypotension, MuscularDystrophy, Myasthenia—Congenital, Myasthenia Gravis, MyelinoclasticDiffuse Sclerosis, Myoclonic Encephalopathy of Infants, Myoclonus,Myopathy, Myopathy—Congenital, Myopathy-Thyrotoxic, Myotonia, MyotoniaCongenita, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with BrainIron Accumulation, Neurofibromatosis, Neuroleptic Malignant Syndrome,Neurological Complications of AIDS, Neurological Complications Of LymeDisease, Neurological Consequences of Cytomegalovirus Infection,Neurological Manifestations of Pompe Disease, Neurological Sequelae OfLupus, Neuromyelitis Optica, Neuromyotonia, Neuronal Ceroid,Lipofuscinosis, Neuronal Migration Disorders, Neuropathy—Hereditary,Neurosarcoidosis, Neurotoxicity, Nevus Cavernosus, Niemann-Pick Disease,Normal Pressure Hydrocephalus, Occipital Neuralgia, Obesity, OccultSpinal Dysraphism Sequence, Ohtahara Syndrome, OlivopontocerebellarAtrophy, Opsoclonus Myoclonus, Orthostatic Hypotension,O'Sullivan-McLeod Syndrome, Overuse Syndrome, Pain-Chronic, Paine,Pantothenate Kinase-Associated Neurodegeneration, ParaneoplasticSyndromes, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis,Paroxysmal Hemicrania, Parry-Romberg, Pelizaeus-Merzbacher Disease, PenaShokeir II Syndrome, Perineural Cysts, Periodic Paralyses, PeripheralNeuropathy, Periventricular Leukomalacia, Persistent Vegetative State,Pervasive Developmental Disorders, Phytanic Acid Storage Disease, Pick'sDisease, Pinched Nerve, Piriformis Syndrome, Pituitary Tumors,Polymyositis, Pompe Disease, Porencephaly, Postherpetic Neuralgia,Postinfectious Encephalomyelitis, Post-Polio Syndrome, PosturalHypotension, Postural Orthostatic, Tachycardia Syndrome, PosturalTachycardia Syndrome, Primary Dentatum Atrophy, Primary LateralSclerosis, Primary Progressive Aphasia, Prion Diseases, ProgressiveHemifacial Atrophy, Progressive Locomotor Ataxia, ProgressiveMultifocal, Leukoencephalopathy, Progressive Sclerosing Poliodystrophy,Progressive Supranuclear, Palsy, Prosopagnosia, Pseudotumor Cerebri,Ramsay Hunt Syndrome I (formerly known as), Ramsay Hunt Syndrome II(formerly known as), Rasmussen's Encephalitis, Reflex SympatheticDystrophy Syndrome, Refsum Disease, Refsum Disease-Infantile, RepetitiveMotion Disorders, Repetitive Stress Injuries, Restless Legs Syndrome,Retrovirus-Associated Myelopathy, Rett Syndrome, Reye's Syndrome,Riley-Day Syndrome, Sacral Nerve Root Cysts, Saint Vitus Dance, SalivaryGland Disease, Sandhoff Disease, Schilder's Disease, Schizencephaly,Seitelberger Disease, Seizure Disorder, Semantic Dementia, Septo-OpticDysplasia, Shaken Baby Syndrome, Shingles Shy-Drager Syndrome, Sjogren'sSyndrome, Sleep Apnea, Sleeping Sickness, Sotos Syndrome, Spasticity,Spina Bifida, Spinal Cord Infarction, Spinal Cord Injury, Spinal CordTumors, Spinal Muscular Atrophy, Spinocerebellar Atrophy,Spinocerebellar, Degeneration, Steele-Richardson-Olszewski Syndrome,Stiff-Person Syndrome, Striatonigral Degeneration, Stroke, Sturge-WeberSyndrome, Subacute Sclerosing Panencephalitis, SubcorticalArteriosclerotic Encephalopathy, SUNCT Headache Swallowing Disorders,Sydenham Chorea, Syncope, Syphilitic Spinal Sclerosis,Syringohydromyelia, Syringomyelia, Systemic Lupus Erythematosus, TabesDorsalis Tardive Dyskinesia, Tarlov Cysts, Tay-Sachs Disease, TemporalArteritis, Tethered Spinal Cord Syndrome, Thomsen's Myotonia, ThoracicOutlet Syndrome, Thyrotoxic Myopathy, Tic Douloureux, Todd's Paralysis,Tourette Syndrome, Transient Ischemic Attack, Transmissible SpongiformEncephalopathies, Transverse Myelitis, Traumatic Brain Injury, Tremor,Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis,Vascular Erectile Tumor, Vasculitis including Temporal Arteritis, VonEconomo's Disease, Von Hippel-Lindau Disease (VHL), Von Recklinghausen'sDisease, Wallenberg's Syndrome, Werdnig-Hoffman Disease,Wernicke-Korsakoff Syndrome, West Syndrome, Whiplash, Whipple's Disease,Williams Syndrome, Wilson's Disease, X-Linked Spinal and Bulbar MuscularAtrophy, or Zellweger Syndrome.

In any aspect or embodiment described herein, the disease or disorder isa neurological disorder with at least one of Huntington's disease,muscular dystrophy, Parkinson's disease, Alzheimer's disease, Battendisease, Injuries to the spinal cord and brain, Seizure disorders,epilepsy, brain tumors, meningitis, autoimmune diseases such as multiplesclerosis, neurofibromatosis, Depression, Amyotrophic Lateral Sclerosis,Arteriovenous Malformation, Brain Aneurysm, Dural ArteriovenousFistulae, Headache, Memory Disorders, Peripheral Neuropathy,Post-Herpetic Neuralgia, Spinal Cord Tumor and Stroke.

In any aspect or embodiment described herein, the disease or disorder isAlzheimer's disease.

What is claimed is:
 1. A bifunctional compound having the chemicalstructure:ULM-L-PTM, or a pharmaceutically acceptable salt thereof, wherein: (a)ULM is: (i) represented by the structure:

wherein: X¹ and X² are each independently selected from a bond, O,NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and SO₂; R^(Y3) and R^(Y4) areeach independently selected from H and linear or branched C₁₋₆ alkyloptionally substituted by 1 or more halogen or C₁₋₆ alkoxyl; R^(P) is 1,2, or 3 groups, each independently selected from the group H, halogen,—OH, and C₁₋₃ alkyl; W³ is an optionally substituted -T-N(R^(1a)R^(1b)),an optionally substituted -T-N(R^(1a)R^(1b))X³, -T-aryl, an optionallysubstituted -T-heteroaryl, an optionally substituted -T-heterocycle, anoptionally substituted —NR¹-T-aryl, an optionally substituted—NR¹-T-heteroaryl, or an optionally substituted —NR¹-T-heterocycle; X³is C═O, R¹, R^(1a), or R^(1b); each R¹, R^(1a), and R^(1b) isindependently selected from H, R^(Y3)C═O, R^(Y3)C═S, R^(Y3)SO,R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O, N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO,and N(R^(Y3)R^(Y4))SO₂, and linear or branched C₁₋₆ alkyl groupoptionally substituted by 1 or more halogen or —OH groups; T is—(CH₂)_(n)—, wherein each one of the methylene groups is optionallysubstituted with one or two substituents independently selected fromhalogen, methyl, a linear or branched C₁₋₆ alkyl group optionallysubstituted by 1 or more halogen or —OH, and an optionally substitutedamino acid side chain; n is 0, 1, 2, 3, 4, 5, or 6; W⁴ is

R_(14a) and R_(14b) are each independently selected from H andoptionally substituted alkyl; W⁵ is a phenyl or a 5-10 memberedheteroaryl; and R₁₅ is H, halogen, CN, OH, NO₂, N R_(14a)R_(14b),OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b),NR_(14a) SO₂R_(14b), optionally substituted alkyl, optionallysubstituted haloalkoxy, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, or optionallysubstituted cycloheteroalkyl,

indicates the site of attachment of L; or (ii) represented by:

wherein: W is CH₂, CHR, C═O, SO₂, NH, or N-alkyl; each X isindependently selected from O, S, and H₂; Y is CH₂, —C═CR′, NH, N-alkyl,N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, or S; Z is O, S,or H₂; G and G′ are independently selected from H, OH, R′OCOOR,R′OCONRR″, linear or branched alkyl optionally substituted with R′,CH₂-heterocyclyl optionally substituted with R′, and benzyl optionallysubstituted with R′; each of Q₁, Q₂, Q₃, and Q₄ independently representsN, CH, or CR; A is H, alkyl, cycloalkyl, Cl, or F; n is 1, 2, 3, or 4;each R is independently selected from —CONR′R″, —OR′, —NR′R″, —SR′,—SO₂R′, —SO₂NR′R″, —CR′R″—, —CR′NR′R″—, -aryl, -heteroaryl, optionallysubstituted linear or branched alkyl, -cycloalkyl, -heterocyclyl,—P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I,—CF₃, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″,—C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂,—CO₂R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅, and—OCF₃, wherein one R is covalently linked to L; R′ and R″ are eachindependently selected from a bond, H, N, N-oxide, optionallysubstituted linear or branched alkyl, optionally substituted cycloalkyl,optionally substituted aryl, heteroaryl, optionally substitutedheterocyclic, or optionally substituted heterocyclyl; and

represents a bond that may be stereospecific ((R) or (S)) ornon-stereospecific; (b) PTM is selected from:

wherein: R¹, R² and R³ are each independently selected from H, methyl,ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; R⁴ and R⁵ are eachindependently selected from H, methyl, ethyl, and halogen; and R⁶ is 1to 2 substituents independently selected from H, methyl, ethyl, andhalogen; and (c) L is a bond or a chemical linking moiety connecting ULMand PTM.
 2. The compound of claim 1, wherein the ULM is represented by:


3. The compound of claim 1, wherein the ULM is represented by thestructure:

wherein: W³ is an optionally substituted aryl, optionally substitutedheteroaryl, or

R₉ and R₁₀ are independently selected from hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, and optionallysubstituted heteroaryl, or R₉, R₁₀, and the carbon atom to which theyare attached form an optionally substituted cycloalkyl; R₁₁ is anoptionally substituted heterocyclic, optionally substituted alkoxy,optionally substituted heteroaryl, optionally substituted aryl,

R₁₂ is H or optionally substituted alkyl; R₁₃ is H, optionallysubstituted alkyl, optionally substituted alkylcarbonyl, optionallysubstituted (cycloalkyl)alkylcarbonyl, optionally substitutedaralkylcarbonyl, optionally substituted arylcarbonyl, optionallysubstituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;R_(14a) and R_(14b) are each independently selected from H or optionallysubstituted alkyl; W⁵ is a phenyl or a 5-10 membered heteroaryl; R₁₅ isH, halogen, CN, OH, NO₂, N R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b),NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionallysubstituted alkyl, optionally substituted haloalkoxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, or optionally substituted heterocycloalkyl; eachR₁₆ is independently selected from H, halogen, optionally substitutedalkyl, hydroxy, and optionally substituted haloalkoxy; o is 0, 1, 2, 3,or 4; each R₁₈ is independently selected from halogen, optionallysubstituted alkoxy, cyano, and optionally substituted alkyl; and p is 0,1, 2, 3, or 4; and

indicates the site of attachment of L.
 4. The compound of claim 1,wherein the ULM has a chemical structure selected from:

wherein: R₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl,optionally substituted hydroxyalkyl, optionally substituted heteroaryl,or haloalkyl; R_(14a) is H, haloalkyl, methyl, fluoromethyl,hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R₁₅ is H, halogen, CN,OH, NO₂, optionally substituted heteroaryl, optionally substituted aryl,optionally substituted alkyl, optionally substituted haloalkyl,optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl; X isC, CH₂, or C═O; R₃ is a bond or an optionally substituted 5 or 6membered heteroaryl; and

indicates the site of attachment of L.
 5. The compound of claim 11,wherein the ULM has the chemical structure:

wherein: R_(14a) is H, haloalkyl, methyl, fluoromethyl, hydroxymethyl,ethyl, isopropyl, or cyclopropyl; R⁹ is H; R₁₀ is H, ethyl, isopropyl,tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; R₁₁ is

or optionally substituted heteroaryl; p is 0, 1, 2, 3, or 4; each R₁₈ isindependently selected from halogen, optionally substituted alkoxy,cyano, and optionally substituted alkyl; R₁₂ is H or C═O; R₁₃ is H,optionally substituted alkyl, optionally substituted alkylcarbonyl,optionally substituted (cycloalkyl)alkylcarbonyl, optionally substitutedaralkylcarbonyl, optionally substituted arylcarbonyl, optionallysubstituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;and R₁₅ is H, halogen, Cl, CN, OH, NO₂, optionally substitutedheteroaryl, optionally substituted aryl,

and

indicates the site of attachment of L.
 6. The compound of claim 1,wherein the ULM is selected from:

wherein: the phenyl ring in ULM-a1 through ULM-a15, ULM-b1 throughULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 is optionallysubstituted with fluorine, C₁₋₃ alkyl, or alkoxy; and

indicates the site of attachment of L.
 7. The compound of claim 1,wherein the ULM has a chemical structure represented by:


8. The compound of claim 1, wherein the ULM has the chemical structure:


9. The compound of claim 1, wherein the ULM has the chemical structure:

wherein: W is CH₂, C═O, NH, or N-alkyl; each R is independently selectedfrom a H and alkyl, wherein one R covalently linked to L; and

represents a bond that may be stereospecific ((R) or (S)) ornon-stereospecific.
 10. The compound of claim 1, wherein the ULM has achemical structure represented by:

wherein

indicate point of attachment to L.
 11. The compound of claim 1, whereinthe L is represented by the formula -(A^(L))_(q)-, wherein:-(A^(L))_(q)-is connected to the ULM and the PM; q is an integer greaterthan or equal to 1; each A is independently selected from CR^(L1)R^(L2),O, S, SO, SO₂, NR^(L3), SO₂NR^(L3), SONR^(L3), CONR^(L3),NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO, CR^(L1)═CR^(L2), C≡C,SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1), NR^(L3)C(═NCN)NR^(L4),NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4), C₃₋₁₁cycloalkyl optionallysubstituted with 1-6 groups independently selected from R^(L1) andR^(L2), C₃₋₁₁heterocyclyl optionally substituted with 1-6 groupsindependently selected from R^(L1) and R^(L2), aryl optionallysubstituted with 1-6 groups independently selected from R^(L1) andR^(L2), and heteroaryl optionally substituted with 1-6 groupsindependently selected from R^(L1) and R^(L2), where R^(L1) or R^(L2),each independently are optionally linked to other groups to form acycloalkyl or heterocyclyl moiety, optionally substituted with 1-4independently selected R^(L5) groups; and each R^(L1), R^(L2), R^(L3),R^(L4), and R^(L5) is independently selected from H, halogen, C₁₋₈alkyl,OC₁₋₈alkyl, SC₁₋₈alkyl, NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl,aryl, heteroaryl, C₃₋₁₁heterocyclyl, OC₃₋₈cycloalkyl, SC₃₋₈cycloalkyl,NHC₃₋₈cycloalkyl, N(C₃₋₈cycloalkyl)₂, N(C₃₋₈cycloalkyl)(C₁₋₈alkyl), OH,NH₂, SH, SO₂C₁₋₈alkyl, P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂,CC—C₁₋₈alkyl, CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃, Si(OH)(C₁₋₈alkyl)₂,COC₁₋₈alkyl, CO₂H, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl,SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl, SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl,CON(C₁₋₈alkyl)₂, N(C₁₋₈alkyl)CONH(C₁₋₈alkyl),N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂, NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂,NHCONH₂, N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NHSO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, and NH SO₂NH₂.
 12. The compoundof claim 1, wherein the L is selected from:

—N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,—O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,—O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—;

wherein: each m, n, o, p, q, and r of L is independently 0, 1, 2, 3, 4,5, or 6, with the proviso that when the number is zero, there is no N—Oor O—O bond; R of L is H, methyl, or ethyl; and X of L is H or F. 13.The compound of claim 1, wherein the L is selected from:


14. The compound of claim 1, wherein the L is selected from:

wherein each n and m of L is independently 0, 1, 2, 3, 4, 5, or
 6. 15.The compound according to claim 1, wherein the L is a polyethylenoxygroup optionally substituted with aryl or phenyl comprising from 1 to 10ethylene glycol units.
 16. A composition comprising a bifunctionalcompound of claim 1 and a pharmaceutically acceptable carrier.
 17. Thecomposition of claim 16, wherein the composition further comprises atleast one of additional bioactive agent
 18. The composition of claim 17,wherein the additional bioactive agent is an anti-neurodegenerativeagent.
 19. The composition of claim 17, wherein the additional bioactiveagent is a P-gp inhibitor.
 20. The composition of claim 19, wherein theP-gp inhibitor is Amiodarone, Azithromycin, Captopril, Clarithromycin,Cyclosporine, Piperine, Quercetin, Quinidine, Quinine, Reserpine,Ritonavir, Tariquidar, Elacridar, or Verapamil.
 21. A method of treatinga Tau-related disease or disorder, comprising administering an effectiveamount of a compound of claim 1 to a subject in need thereof, whereinthe compound effectuates degradation of Tau protein thereby treating orameliorating at least one symptom of a Tau disease or disorder, whereinthe Tau disease or disorder is associated with Tau accumulation andaggregation.
 22. The composition of claim 21, wherein the disease ordisorder is a neurodegenerative disease associated with Tau accumulationand aggregation.
 23. The composition of claim 21, wherein the disease ordisorder is a neurological disorder with at least one of Huntington'sdisease, muscular dystrophy, Parkinson's disease, Alzheimer's disease,Batten disease, Injuries to the spinal cord and brain, Seizuredisorders, epilepsy, brain tumors, meningitis, autoimmune diseases suchas multiple sclerosis, neurofibromatosis, Depression, AmyotrophicLateral Sclerosis, Arteriovenous Malformation, Brain Aneurysm, DuralArteriovenous Fistulae, Headache, Memory Disorders, PeripheralNeuropathy, Post-Herpetic Neuralgia, Spinal Cord Tumor and Stroke. 24.The composition of claim 21, wherein the disease or disorder isAlzheimer's disease.